CA2896038C - Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof - Google Patents
Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof Download PDFInfo
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- CA2896038C CA2896038C CA2896038A CA2896038A CA2896038C CA 2896038 C CA2896038 C CA 2896038C CA 2896038 A CA2896038 A CA 2896038A CA 2896038 A CA2896038 A CA 2896038A CA 2896038 C CA2896038 C CA 2896038C
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- Prior art keywords
- sodium hyaluronate
- polymer matrix
- bio
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- active ingredient
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- 239000000203 mixture Substances 0.000 title claims abstract description 177
- 229920002385 Sodium hyaluronate Polymers 0.000 title claims abstract description 173
- 229940010747 sodium hyaluronate Drugs 0.000 title claims abstract description 173
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 173
- 239000011159 matrix material Substances 0.000 title claims abstract description 106
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims abstract description 87
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Abstract
The present invention relates to stable polymer matrix compositions comprising high concentrations (from about 1.5% w/w to about 3.5% w/w) sodium hyaluronate obtained from a Streptococcus zooepidemicus source and a non-ionic polymer. The polymer matrix composition further comprises polyethylene glycol and methylparaben, and utilizes ingredients that are of pharmaceutical or compendial grade. The polymer matrix compositions may optionally comprise an active ingredient. The present polymer matrix compositions may be used in the treatment of wounds, burns, certain dermatological conditions, vaginal dryness, and in topical, transdermal delivery and sustained release of active ingredients.
Description
POLYMER MATRIX COMPOSITIONS COMPRISING A HIGH
CONCENTRATION OF BIO-FERMENTED SODIUM HYALURONATE AND
USES THEREOF
FIELD OF THE INVENTION
[0001] The present invention relates to polymer matrix compositions comprising sodium hyaluronate. More particularly, the present invention relates to polymer matrix compositions comprising sodium hyaluronate obtained from a bacterial source and that are useful in the treatment of wounds and incisions, treatment of pain, transdermal delivery of active ingredients, sustained release of active ingredients, and preparation of personal lubricants.
BACKGROUND OF THE INVENTION
CONCENTRATION OF BIO-FERMENTED SODIUM HYALURONATE AND
USES THEREOF
FIELD OF THE INVENTION
[0001] The present invention relates to polymer matrix compositions comprising sodium hyaluronate. More particularly, the present invention relates to polymer matrix compositions comprising sodium hyaluronate obtained from a bacterial source and that are useful in the treatment of wounds and incisions, treatment of pain, transdermal delivery of active ingredients, sustained release of active ingredients, and preparation of personal lubricants.
BACKGROUND OF THE INVENTION
[0002] Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide (also commonly referred to as glycosaminoglycan). It has been isolated by various methods from numerous tissue sources including vitreous humor, skin, synovial fluid, serum, chicken combs, shark skin, umbilical cords, tumors, hemolytic streptococci from pigskin, whale cartilage, and the walls of veins and arteries. HA may, however, also be synthesized artificially or made by recombinant technology. Moreover, it is known that HA may also be manufactured by fermentation of selected Streptococcus zooepidemicus bacterial strains (see U.S. Pat. No. 4,517,295 issued to Bracke et al.), and can readily be converted to its sodium salt. The repeating unit of the HA molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glycosamine. Because HA has a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions.
[0003] Fractions of HA, including its sodium salt, are known to form a stable polymer matrix when combined with a non-ionic polymer such as hydroxyethyl cellulose or hydroxypropyl cellulose. Such polymer matrix formulations are known to be useful in preparing compositions for various applications for human and animal use.
[0004] For example, a formulation containing sodium hyaluronate and hydroxyethylcellulose was formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel for applying to wounds to promote wound healing. In addition, polymer matrices of HA formulated with other active ingredients are known to be useful as topical drug formulations for delivering the active ingredients to sites below the dermal level of the skin. HA polymer matrix topical active ingredient formulations for trans-dermal delivery of active ingredients are disclosed for example in U.S. Pat. 5,897,880, U.S. Pat.
6120,804, U.S. Pat. 6,387,407, and U.S. Pat. 6,723,345. HA polymer matrices formulated with other active ingredients are also known to be useful as formulations for sustained release of the pharmaceutical agents. HA polymer matrix formulations for sustained release delivery of active ingredients are disclosed in U.S. Pat. 6,063,405, U.S. Pat. 6,335,035, and U.S. Pat.
6,007,843.
100051 Preparing sodium hyaluronate polymer matrix formulations presents many challenges. Initially, in the 1980s only HA obtained from animal sources was available commercially, and many of the formulations were delivered by injection, or used as drops in the eye, rather than for topical use for dermatological conditions. The natural HA used in various formulations has usually been obtained from rooster combs. The rooster comb (also known as a chicken comb) is an avian source and as such is of animal origin. As a result, sodium hyaluronate formulations manufactured using sodium hyaluronate from rooster combs have been known to cause allergies and carry other risks associated with products of animal origin, namely a risk of transmission of animal diseases to humans. Consequently, the currently approved topical products containing sodium hyaluronate formulations available on the market are contra-indicated for those patients who are hypersensitive to sodium hyaluronate of animal origin.
100061 Moreover, sodium hyaluronate is difficult to formulate in high concentrations above 1.5% w/w, due to the difficulty in manufacturing a formulation that maintains stability and is not too viscous for normal use when packaged in a tube. For this reason many of the commercial formulations on the market have a concentration of HA or sodium hyaluronate well below 1%
w/w, and many in fact have a concentration at around 0.2% w/w. To the inventors' knowledge, there are no products currently on the market that contain more than 1.5% w/w sodium hyaluronate. When not mixed and manufactured properly, a high HA or sodium hyaluronate concentration formulation will quickly break down, and therefore the percentage of HA or sodium hyaluronate in the formulation will fall below the acceptable limit (+/-10% of original amount), resulting in a very short shelf life for the product.
Formulations containing a high concentration of sodium hyaluronate therefore present a challenge due to the instability of the matrix. This results in inconsistencies in the matrix formulation and impairs the ability of sodium hyaluronate formulations to perform their functions. For example, when applied to wounds to promote healing, a sodium hyaluronate polymer matrix formulation helps to maintain a moist wound environment, an effect that is dependent on the formulation maintaining its high level of sodium hyaluronate concentration. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing. However, due to their instability and the resulting drop in the level of sodium hyaluronate that occurs as the formulation breaks down, high concentration sodium hyaluronate formulations are not effective in maintaining a moist environment. When formulated for the delivery of a drug, the inconsistency of high concentration sodium hyaluronate formulations reduces the ability of such formulations to allow the drug to diffuse through the tissue when administered, thereby impairing their ability to achieve the therapeutic dose.
100071 In addition, the sodium hyaluronate polymer matrix formulation product formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel was withdrawn from the market due to problems with the formulation.
[0008] Therefore, a need exists for a method for formulating a sodium hyaluronate polymer matrix containing a high concentration of sodium hyaluronate that can be manufactured and sold commercially.
SUMMARY OF THE INVENTION
[0009] The present invention relates to stable polymer matrix compositions comprising a high concentration (about 1.5% to about 3.5% w/w) of sodium hyaluronate obtained from a bacterial Streptococcus zooepidemicus or Bacillus subtilis source (bio-fermented sodium hyaluronate), a non-ionic polymer, said polymer matrix compositions further comprising polyethylene glycol and methylparaben.
[0010] In one aspect of the present invention, the polymer matrix compositions of the present invention comprise components which are of compendial (USP
or Ph. Eur.) and/or of pharmaceutical grade. In a further aspect of the invention, the polymer matrix compositions comprise components of certain specifications.
100111 In one aspect, polymer matrix compositions of the present invention may be used in the treatment of wounds, burns, and certain dermatological conditions.
[0012] In another aspect of the present invention, the polymer matrix compositions comprise an active ingredient. In this aspect of the invention, the polymer matrix compositions may be used for trans-dermal delivery, topical, and sustained release delivery of the active ingredient.
[0013] In some aspects, the polymer matrix compositions may be used for the treatment of musculoskeletal pain. A further aspect of the present invention relates to the use of the polymer matrix compositions in the treatment of vaginal dryness.
[0014] In a further aspect, the present invention relates to methods for preparing stable polymer matrix compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The inventors determined that the product IPM Wound Gel could not be successfully formulated because the product was made from naturally sourced sodium hyaluronate ("natural sodium hyaluronate") and because the testing regimen was not sufficient and raw materials were not of sufficient quality. The natural sodium hyaluronate was produced from rooster combs (which is an animal origin source) and was of cosmetic grade. The natural sodium hyaluronate was found to be more prone to microbiological contamination including that from the manufacturing facility and surrounding environment. This led to microbiological failure of the product rendering the product unsafe and not useful. Moreover, the product IPM Wound Gel used ingredients that were of insufficient or inconsistent grade. Also, testing to determine the quality of the IPM Wound Gel Product was insufficient to ensure a stable product of sufficient quality.
[0016] The inventors unexpectedly discovered that sodium hyaluronate polymer matrix compositions can be advantageously formulated using bio-fermented sodium hyaluronate obtained from strains of Streptococcus zooepidemictts or Bacillus subtilis bacteria (herein referred to as "bio-fermented sodium hyaluronate").
[0017] The inventors further determined that sodium hyaluronate polymer matrix compositions can be advantageously formulated by using ingredients of sufficient quality, i.e., ingredients of compendia! (USP or Ph. Eur.) and/or pharmaceutical quality, including bio-fermented sodium hyaluronate, and through the use of validated assays methods for testing the amount of sodium hyaluronate and methylparaben in the formulation, as well as through compliance with Bacterial Endotoxin Test ("BET"), and microbiological test limits, including for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp., as well as compliance with other parameters.
[0018] The inventors further developed a process for formulating a polymer matrix composition containing a high concentration (i.e., between about 1.5%
w/w to about 3.5% w/w) of sodium hyaluronate and produced a stable polymer matrix composition containing a high concentration of sodium hyaluronate.
[0019] Sodium hyaluronate (CAS Number: 9067-32-7, molecular formula [C14H20N1 'Nab) consists of a linear polysaccharide, whose basic unit is a disaccharide of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic (1-3) bond. The disaccharides units are linearly polymerized by hexosaminidic (1-4) linkages, as shown in Formula 1:
[0020]
coAki 01:00,110) õ0 OH
[0021] Sodium hyaluronate is a white or almost white, very hygroscopic powder or fibrous aggregate. It is odorless and the pH of the 5% solution is in the range of 5.0¨ 8.5. Sodium hyaluronate is easily soluble in cold water and insoluble in organic solvents. Sodium hyaluronate of high quality, i.e., BET
<0.5 EU/g microbial qualit., may be obtained from commercial suppliers.
100221 The process of obtaining bio-fermented sodium hyaluronate can vary, but in general, the preparation involves the following steps: fermenting selected Streptococcus zooepidemicus bacterial strains; selecting the sodium hyaluronate crude product obtained from fermentation; purifying the crude product by filtration; precipitating sodium hyaluronate with an organic solvent; and drying. Bio-fermented sodium hyaluronate obtained from Streptococcus zoopidemicu,; is available commercially from suppliers such as QUFU, Freda, and Contipro.
100231 As an example, U.S. Pat. No. 4,517,295 to Bracke et al. discloses the preparation of hyaluronic acid in high yield from Streptococcus bacteria by fermenting the bacteria under anaerobic conditions in a CO2 enriched growth medium, separating the bacteria from the resulting broth and isolating the hyaluronic acid from the remaining constituents of the broth. Separation of the microorganisms from the hyaluronic acid is facilitated by killing the bacteria with trichloroacetic acid. After the removal of the bacteria cells and concentration of the higher molecular weight fermentation products, the hyaluronic acid is isolated and purified by precipitation, re-suspension and re-precipitation.
100241 One particular fraction of bio-fermented sodium hyaluronate that exhibits excellent matrix formation according to the present invention is sodium hyaluronate having an average molecular weight between about 600,000 Daltons to abOut 800,000 Daltons. Bio-fermented sodium hyaluronate having an average molecular weight of 500,000 to 1,000,000 Daltons has also been found to be acceptable in the formulations of the present invention.
100251 In addition to bio-fermented sodium hyaluronate, polymer matrix formulations of the present invention include a non-ionic polymer. Non-ionic polymers suitable for use in formulations of the present invention include polyvinylpyrrolidones, poloxamers, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymers, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymers, polyacrylamides, polyethylene oxide copolymers, neutralized polyacrylic acids, polysorbates, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) and alpha, omega-dialkyl-ethoxylates, or mixtures thereof.
[0026] Polyvinylpyrrolidones suitable for use with the present invention include PVP K-90, PVP K-17, and polyvinyl pyrrolidone-vinyl acetate (PVP-VA) copolymer.
[0027] Cellulose derivatives-suitable for use with the present invention include hydroxyethylcellulose, hydroxypropylmethylcellulose, ethyl(hydroxyethyl)cellulose, and methyl cellulose.
[0028] Sorbitol based polymers suitable for use with the present invention include Neosorb.
[0029] Polyacrylic acids suitable for use with the present invention include neutralized Carbopol 980 and Carbopol 940.
[0030] Polysorbates suitable for use with the present invention include Polysorbate 20 (USP/Ph. Eur.), Polysorbate 21, Polysorbate 40 (USP/Ph.
Eur.), Polysorbate 60 (USP/Ph. Eur.), Polysorbate 61, Polysorbate 65, Polysorbate 80 (USP/Ph Eur.), Polysorbate 81, Polysorbate 85, and Polysorbate 120.
[0031] Hydroxyethylcellulose ("HEC") is a particularly preferred non-ionic polymer for use with the present invention.
[0032] It is believed that there are many such non-ionic polymers that can be used to successfully form the polymer matrix formulations of the present invention. As such, included in the present invention are any non-ionic polymers that can successfully form a polymer matrix with sodium hyaluronate.
[0033] Other suitable ingredients for use in the manufacture of the polymer matrix compositions of the present invention include stabilizers and fillers such as methylparaben, benzyl alcohol, polyethylene glycol, methoxypolyethylene glycol, and purified water. Preferably, ingredients used in the bio-fermented sodium hyaluronate polymer matrix compositions of the present invention conform to the compendial standards (USP or Ph. Eur.) [0034] When compared to the product IPM Wound Gel, the bio-fermented sodium hyaluronate used in the preferred embodiment of compositions of the present invention is of compendial or pharmaceutical grade quality. All raw material used in the formulations of the present invention are of better microbiological quality and all are of compendial and/or pharmaceutical grade. The following Table 1 compares the changes made in specifications of raw materials from the formulation used in the product IPM Wound Gel to the formulation of the present invention.
Table 1. Changes to specification.; of raw materials used in the formulation of the present invention in comparison to those used in the product IPM Wound Gel.
Sodium hyaluronate bio-fermented 1PM Wound Gel formulation of the present invention Sodium hyaluronate Grade: Cosmetic grade Grade: Pharmaceutical grade (Ph.
Eur.) Nucleic acid: <0.5% (Ph. Eur.) Protein content < 5% Protein content < 0.3% (Ph. Eur.) TYMC < 50 cfu (colony forming units)/g TYMC < 10 cfu/g (Ph. Eur.) E.coli : Negative Staphylococcus aureus: Absence (Ph.
Eur.) Pseudomonas aeruginosa: Absence (Ph.
Eur.) Escherichia coli: Absence (Ph. Eur.) Salmonella sp.: Absence (Ph. Eur.) Bacterial Endotoxin Test (BET) < 0.5 IU/mg Hydroxyethylcellulose (HEC) Sodium hyaluronate bio-fermented 1PM Wound Gel formulation of the present invention TAMC (Total Aerobic Microbial Count) TAMC < 100 cfu/g (USP/Ph. Eur.) <1000 cfu/g Polyethylene Glycol 200 (PEG 200) PEG 200 or PEG 400 PEG 200 Limit of ethylene glycol and diethylene glycol (combined): < 0.25% w/w (USP) TAMC < 100 cfu/mL (USP) TYMC < 10 cfu/mL (USP) Methylparaben TAMC < 100 cfu/mL (USP/Ph. Eur.) TYMC < 10 cfu/mL (USP/Ph. Eur.) Purified water TAMC < 100 cfu/mL (USP/Ph. Eur.) BET < 0.25 EU/mL (USP/Ph. Eur.) [0035] The grade of PEG used with IPM Wound Gel was intermittently PEG
400 which led to failure of product due to instability. The matrix formed were not stable. The PEG used with the preferred embodiment of formulations of the present invention is of better purity in that the restricted substances, namely, ethylene glycol and diethylene glycol are well controlled.
[0036] Sodium hyaluronate used with the IPM Wound Gel was of cosmetic grade. In the preferred embodiment, the present invention uses sodium hyaluronate of pharmaceutical grade with consistent quality and content of nucleic acid and protein. In the preferred embodiment of the present invention, the TYMC microbial count is better controlled, and all the specified microorganisms are tested for their absence. Additionally, in the preferred embodiment of the present invention, BET is tested, and the protein content of sodium hyaluronate has been significantly reduced (from 5% limit for IPM
Wound Gel to 0.3% limit for the preferred embodiment of the present invention).
[0037] In regard to HEC used in the preferred embodiment of the present invention, there is a better control of microbial count (<100 cfu/g) than with the HEC used with IPM Wound Gel (<1000 cfu/g) provided by the raw material supplier, and the hence the formulation of the present invention in the preferred embodiment was found to be significantly better quality.
[0038] In the preferred embodiment of the present invention, methylparaben raw material is tested for TAMC and TYMC tests to ensure that only good quality raw material is used in the manufacture of the formulation in the preferred embodiment of the present invention.
[0039] Additionally, in the preferred embodiment of the present invention, purified water is better controlled microbiologically by performing additional tests TAMC and BET.
[0040] The bio-fermented sodium hyaluronate polymer matrix formulation is a clear viscous, odorless, aqueous gel composed principally of sodium hyaluronate, a derivative salt of hyaluronic acid. The formulation of bio-fermented sodium hyaluronate is a polymer matrix made up of negatively charged polymer, namely, sodium hyaluronate, and a non-ionic polymer, such as HEC. In other words, sodium hyaluronate (as a negatively charged polymer) forms part of the polymer matrix in combination with a non-ionic polymer, such as HEC, and it helps to maintain the moist environment through the matrix.
[0041] The concentration of sodium hyaluronate in the polymer matrix is from about 1.5% to about 3.5% w/w, and the concentration of the non-ionic polymer, other than HEC, is from about 0.1% w/w to about 2.0% w/w, preferably from about 0.7% w/w to about 1.3% w/w. The concentration of HEC is from about 0.1% w/w to about 1.5% w/w, preferably from about 0.7%
w/w to about 1.3% w/w.
[0042] Preferably, non-ionic polymers such as HEC are of compendial or pharmaceutical grade. Where non-ionic polymers are not available in compendial or pharmaceutical grade, non-ionic polymers of best available quality should be used.
[0043] The viscosity of bio-fermented sodium hyaluronate polymer matrix formulation should be in the acceptable limits or range so that the matrix is stable and is easy to apply on the skin, wound, or other tissue. The formulation should also have a viscosity that can be handled easily during manufacturing and filling. The viscosity range has been investigated. It was determined that the formulation of the present invention should have a viscosity of about 10,000 to 50,000 cps (cP) when tested at room temperature. The therapeutically useful pH range of the formulation was set at 5.0 to 7Ø
[0044] Preferably, the bio-fermented sodium hyaluronate polymer matrix formulation comprises sodium hyaluronate (2.5%, w/w), HEC (1% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w). The test results found that the average viscosity of this bio-fermented sodium hyaluronate formulation is 30,000 cps, i.e. exactly in the middle of the range (10,000 ¨ 50,000 cps). It is well known that molecular weight of sodium hyaluronate and concentration of sodium hyaluronate have a direct effect on the viscosity of the product.
[0045] The solutions used to prepare the gels of the present invention may be prepared in a variety of ways. The non-ionic polymer such as HEC may be dissolved in water, mixed with anionic or negatively charged sodium hyaluronate solution to form the sodium hyaluronate/non-ionic polymer matrix, and then the optional active ingredient may be added or loaded to the system.
[0046] The preparation procedure may involve dissolving a non-ionic polymer such as HEC in water at a low to medium speed for few hours (about 1 to about 2 hours).
[0047] Separately, sodium hyaluronate may be slowly added to water while stirring at high speed, followed by stirring at medium speed for few hours (about 2 hours), followed by stirring at low speed for a long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[0048] The non-ionic polymer such as HEC solution may be added to the sodium hyaluronate solution and mixed at medium speed followed by mixing at low to medium speed for long period (from about 4 hours to about 15 hours) until a homogenous solution is produced.
[0049] Conventional pharmaceutically acceptable emulsifiers, suspending agents, solvents (such as polyethylene glycol 200), antioxidants (such as sodium meta-bisulfate) and preservatives (such as benzyl alcohol, methylparaben) may then be added to this system.
[0050] When formulated with an active ingredient as a system for transdermal or sustained release of the active ingredient, using safe techniques, the active ingredient (e.g., 3% diclofenac sodium) may be slowly added to the above sodium hyaluronate/non-ionic polymer matrix mixture while increasing the speed to high speed, and the addition of the entire quantity of the active ingredient should be completed within a short duration (about 15 minutes).
[0051] Once all the components are blended together, such as by mixing at low to medium speed for from about 2 hours to about 20 hours, the system is filled into tubes. The resulting system is clear to slightly hazy, colourless, viscous, odorless gel which are found to be stable on storage for a few years (from 18 months to 4 years).
[0052] Preferably, a bio-fermented sodium hyaluronate polymer matrix formulation is prepared as follows. First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours).
Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate in a steady flow to the mixture gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour).
Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyaluronate =
polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[0053] In a separate container dissolve 1% HEC in purified water while stirring at medium speed and mix well. Continue stirring for a few hours (from about 1 to about 2 hours).
[0054] The resulting HEC solution is added to the sodium hyaluronate solution and mixed at medium speed followed by low speed for a long period (about 4 hours) until a homogenous solution is produced.
[0055] Add polyethylene glycol into the mixture while mixing at a medium speed. Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed for a few hours (minimum of about 3 hours).
The bulk gel is then filled in tubes or bottles and capped.
[0056] The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of pharmaceutical compositions, medical device compositions, natural health product compositions, and dietary supplement compositions. In topical applications, the polymer matrix compositions of the present invention serve to maintain moist wound environment. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing process and relief from certain dermatological conditions. The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be used for topical application in the treatment of many types of ulcers (wounds), including venous stasis, diabetic wounds, and post-operative incisions, and in anti-aging treatments. The invention has shown to be especially effective in hard-to-heal wounds.
100571 More particularly, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown to be useful in topical applications for the management of minor burns (1' degree burns), minor abrasions, minor cuts, and in helping to relieve dry waxy skin irritations association with dry skin conditions. Furthermore, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown be useful in topical applications for the management of exudating wounds such as leg ulcers, pressure ulcers, diabetic ulcers, surgical wounds (post-operative and donor sites), mechanically or surgically debrided wounds, second degree burns, and the management and relief of burning, itching and pain associated with various types of dermatoses, including atopic dermatitis, allergic contact dermatitis, and radio-dermatitis.
[0058] In other aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be also used in the manufacture of a system for a sustained release delivery of an active ingredient, and in the manufacture of a system for transdermal delivery of an active ingredient.
[0059] In additional aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of personal lubricants for use in the management of symptoms of female sexual dysfunction.
[0060] When formulated with an active ingredient as a system for transdermal delivery of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation is believed to form a matrix which microencapsulates, suspends, and/or entraps the active ingredient such that when it is administered, it is slowly released into the systemic circulatory system or muscular tissue providing a method of delivering an active ingredient to an affected site in the body through the skin.
[0061] The active ingredient may be added either directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC
or it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC and mixed well. The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be ,..dded to this system. One particularly non-limiting effective material for solubilizing water insoluble drugs is methoxypolyethylene glycol (MPEG). Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, if required, and stored for future use.
[0062] The formulations of this invention formulated with an active ingredient for trans-dermal delivery of an active ingredient may potentially be used to treat a variety of mammal and animal conditions and physical states. These systems may .have a particular application to pain management, namely the treatment and alleviation of pain associated with any disease, condition or physical state.
[0063] Without being limited to the specific pain being treated, the preparations of this invention formulated with an active ingredient for transdermal delivery may treat the following non-limiting locations or sources of pain below the dermal level of the skin, including, but not limited to knees, ankles, hands, feet and neck.
[0064] In addition to treating disorders associated with pain below the dermal level of the skin, the preparations of this invention formulated with an active ingredient for transdermal delivery may be used to treat a wide variety of dermatologic disorders as well as many types of ulcers (wounds) including venous stasis and diabetic wounds. The invention has shown to be especially effective in hard to heal wounds. Exemplary, non-limiting disorders that may potentially be treated with the preparations of this invention formulated with an active ingredient for transdermal delivery include dermatitis conditions such as: Contact Dermatitis; Atopic Dermatitis; Radio Dermatitis; Seborrheic Dermatitis; Nummular Dermatitis; Chronic Dermatitis of Hands and Feet;
Generalized Exfoliative Dermatitis; Stasis Dermatitis; and Localized Scratch Dermatitis; bacterial infections of the skin, such as: Staphylococcal Diseases of the Skin, Staphylococcal Scalded Skin Syndrome; Erysipelas; Folliculitis;
Furuncles; Carbuncles; Hidradenitis Suppurativa; Paronychial Infections and Erythrasma; superficial fungal infections such as: Dermatophyte Infections;
Yeast Infections; Candidiasis; and Tinea Versicolor; parasitic infections of the skin such as: Scabies; Pediculosis; and Creeping Eruption; disorders of hair follicles and sebaceous glands such as: Acne; Rosacea; Perioral Dermatitis;
Hypertrichosis; Alopecia; Pseudofolliculitis Barbae; and Keratinous Cyst;
scaling papular diseases, such as: Psoriasis; Pityriasis Rosea; and Lichen Planus; pressure sores; benign tumors and malignant tumors.
[0065] A wide variety of active ingredients which may be administered topically may be used in the transdermal delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including benzocaine, tetracaine, mepivacaine, prilocaine, etidocaine, bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat.
No. 3,652,762), phenacetin and salicylamide; nonsteroidal anti-inflammatories (NSAIDS) selected from the group consisting of naproxen, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, phenacetin, salicylamide, and indomethacin; antibiotics including amebicides, broad and medium spectrum, fungal medications, monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa;
metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatis-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex including vitamin B5 and B3 (Niacin), vitamin C, vitamin B12 and folic acid and veterinary formulations.
100661 Doses may vary from patient to patient depending on the type and severity of the condition being treated and the active ingredient being administered. Generally, doses of 1 ml to 75 ml may be administered with preferred doses using 2 to 25 ml of the gelled matrix system.
[0067] When formulated with another active ingredient as a system for sustained release of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation may allow an effective therapeutic level of an active ingredient to be administered once over at least a 24 hour to several day interval. It is believed that the bio-formulated sodium hyaluronate polymer matrix formulation forms a matrix which microencapsulates, suspends and/or entraps the active ingredient such that when it is administered it is slowly released into the systemic circulatory system or muscular tissue providing a sustained and prolonged active ingredient release rate.
[0068] A wide variety of active ingredients may be used in the sustained delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including those used in caudal, epidural, inhalation, injectable, retrobulbar, and spinal applications, such as bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat. No.
3,652,762), phenacetin and salicylamide; anti-inflammatories selected from the group consisting of naproxen and indomethacin; antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxy lamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fiimarate and triprolidine;
antitussive selected from the group consisting of dextromethorphan hydrobromide and guaifenesin; expectorants such as guaifenesin;
decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine; antibiotics including amebicides, broad and medium spectrum, fungal medications, =
monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives;
bronchodilators such as theophylline, albuterol and terbutaline;
cardiovascular preparations such as diltiazem, propranolol, nifedepine and clonidine including alpha adrenoceptro agonist, alpha receptor blocking agent, alpha and beta receptor blocking agent, angiotensin converting enzyme inhibitors, beta blocking agents, calcium channel blocker, and cardiac glycosides; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa;
metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatin-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex, vitamin C, vitamin B12 and folic acid and veterinary formulations. Dosage forms may also involve the use of bupivacaine, lidocaine, vitamin B12, methyl prednisolone and adenosine-5-monophosphate sodium.
[0069] The active ingredient may be added directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC
or else it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be added to this system.
Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, and stored for future use.
100701 The dosage form of this invention, in solution or suspension form, may be used topically or by injection intramuscularly, epidurally or subcutaneously. Dosages may vary from patient to patient depending on the type and severity of the condition being treated and drug being administered.
The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered.
100711 The formulations of this invention formulated with an active ingredient for sustained delivery of an active ingredient may potentially be used to treat a variety of animal conditions and physical states. These systems may potentially have particular application to pain management, namely the treatment and alleviation of pain associated with any disease condition or physical state.
[0072] Without being limited to the specific pain being treated, the preparations of this invention when formulated with an active ingredient for sustained delivery of an active ingredient may potentially treat the following non-limiting locations or sources of pain: abdominal, such as in appendicitis, dysmenorrhea, musculoskeletal, pelvic, peptic ulcer, psychogenic, and urologic; acute; arm; backache; cancer; cardiac (myocardial ischemia); chest;
dental; ear; esophageal; eye; face; head; and neck; in fibromyalgia; foot; and leg; heel; ischemic pain such as in myocardial, peripheral arterial, low back, in mitral valve prolapse, in myocardial infarction, myofascial pain syndrome (fibromyalgia, fibromyositis), neck, neuropathic, neurotransmitter abnormality, nociceptive, and nocturnal pain; pelvic; pericardial; in peripheral arterial disease; phantom limb; pleuritic; polyneuropathy; postmastectomy syndrome; postoperative; psychogenic; in pulmonary embolism; in renal disease, such as colic; root avulsions; shoulder; stump; thalamic; in toes;
and toothache.
[0073] Besides chronic and intractable pain where injections of the formulation of the present invention for sustained delivery of an active ingredient may be required, the present sustained delivery formulations may potentially be used to aid in post-surgical pain treatments. With regard to uses after surgery, the formulations may be used following abdominal, cervical, thoracic or cardiac surgery, whereby multiple layers of tissue, as being sewed back together, are treated with the system. Such treatments may aid in a patient's recovery by not on:y avoiding addictive drug use such as a morphine drip, but result in the immediate and long term relief of pain to enable rapid rehabilitation.
[0074] The formulations of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art.
[0075] An effective but nontoxic amount of the system is employed in treatment. The dose regimen for administering drugs or treating various conditions may be selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the route of administration and the particular formulation or combination of active ingredients employed. Determination of the proper dose for a particular situation is within the skill of the art. Generally, amounts of the active ingredient may vary from 0.0001% to about 50% by weight of the system.
[0076] The bio-fermented sodium hyaluronate polymer matrix formulation of the present invention was found to be stable and safer than that used in the known Ionic Polymer Matrix (IPM) Wound Gel based on various testing such as Bacterial Endotoxin Test (BET), biocompatibility tests (Example 1, Example 2, and Example 3) and microbial bio-burden test (Example 7), and is of better quality based on validated chemical test (Example 5 and 6) and stability data of the product at regular interval of time (Example 4).
[0077] A new BET has been carried out in addition to the existing test methods used with the Ionic Polymer Matrix (IPM) Wound Gel product in order to ensure that the bio-fermented sodium hyaluronate polymer matrix formulation of the present invention meets the acceptable BET test limits and hence potentially reduces the incidence of pyrogenicity in the patients. Previously, there were no BET test limits set for the Ionic Polymer Matrix (IPM) Wound Gel product. Only positive or negative bacterial endotoxin test results were identified. The BET test results carried out with the bio-fermented sodium hyaluronate polymer matrix formulation product and bio-fermented sodium hyaluronate raw material indicated that the products pass the BET test. Both the raw material bio-fermented sodium hyaluronate and the finished bio-fermented sodium hyaluronate polymer matrix formulation product were tested for BET with stringent limits. The BET test were validated.
[0078] In addition, no microbiological tests for specific microorganisms or the absence of specific microorganisms were previously performed on the Ionic Polymer Matrix (IPM) Wound Gel product. Microbiological testing performed on each batch or lot of the bio-fermented sodium hyaluronate polymer matrix formulation product included all the tests as per USP<61>
(Total Aerobic Microbial Count (TAMC) and Total Combined Yeast and Mould Count (TYMC)) and USP<62> (Absence of Staphylococcus aureus, Pseudomonas aeruginosa, E. coli and Salmonella). The product passed these tests. The stability of the bio-fermented sodium hyaluronate polymer matrix formulation has now also been investigated and the product has demonstrated acceptable stability.
[0079] Previous the test methods used for the determination of sodium hyaluronate and methylparaben in the Ionic Polymer Matrix (IPM) Wound Gel product were found to be not precise, accurate or linear since the test methods were not validated. Validated analytical test methods were also developed and applied to the determination of hyaluronic acid content (see Example 13 and Example 5) and also for the determination of methylparaben content (see Example 14 and Example 6) in the bio-fermented sodium hyaluronate polymer matrix formulation.
[0080] Application of the bio-fermented sodium hyaluronate polymer matrix formulation was shown in a clinical study showing improvement in closure of incision lines in patients with toe amputations due to diabetes complications (Example 8).
[0081] In summary, the disclosed process allows for preparing sodium hyaluronate polymer matrix concentration having a high concentration of sodium hyaluronate, i.e., from about 1.5% to about 3.5% w/w. There is a significant improvement in the quality and safety of bio-fermented sodium hyaluronate polymer matrix formulation from the known Ionic Polymer Matrix (IPM) Wound Gel due to the change in the source of sodium hyaluronate from avian (rooster comb) to a bio-fermented source obtained from a bacterial fermentation process. Additional improvements are due to the development and application of additional quality testing such as BET and bioburden test (USP 62) and improved Biocompatability test (Cytoxicity test) results, the development and application of test methods for sodium hyaluronate and the preservative methylparaben, and the use of compendial or pharmaceutical grade raw materials.
[0082] Table 2 below summarizes the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel.
Table 2. Summary of the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Bacterial Endotoxin Test BET: Negative BET test limits established.
The test method was based old Rabbit The test method is based on LAL test Pyrogenicity test. (Limulus amebocyte lysate test) method which is better quantified.
BET method validated Test for Specified Microorganisms Test for Specified Microorganisms including:
Pseudomonas aeruginosa: Negative Staphylococcus aureus: Negative E. coli: Negative Salmonella: Negative Conducted per USP<62>/Ph. Eur.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Validated Test Methods Analytical test method validated for the determination of sodium hyaluronate content in the sodium hyaluronate bio-fermented formulation.
Analytical test method validated for the determination of methylparaben content in the sodium hyaluronate biofermented formulation.
Viscosity Viscosity (II) = 10, 000 ¨ 50,000 cps (recorded).
Anti-microbial Effectiveness Test (AET) AET: Meets USP requirements (stability test) (USP <51>) Methylparaben test Methylparaben test (Limit 90¨ 110%) (stability test) Biocompatibility Test Test for Skin Irritation, Guinea pig Test for Skin Irritation, Guinea pig Maximization Sensitization Test and Maximization Sensitization Test and Cytotoxicity Test were performed. Cytotoxicity Test were performed.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention However, Cytotoxicity test showed that the test article had a smaller zone of lysis (i.e. less cytotoxic) as compared to the IPM Wound Gel.
Stability 1 year long-term stability data available. 18 months long-term stability data available.
100831 In the examples below, results of testing of bio-fermented sodium hyaluronate polymer matrix formulation comprising sodium hyaluronate (2.5%, w/w), hydroxyethyl cellulose (I% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w) made from raw materials of preferred grades and by preferred process of the present invention (referred to as the "test article", also referred to "IPM
Wound Gel Bio") are presented.
Example 1: Test for Skin Irritation [0084] The test article, bio-fermented sodium hyaluronate polymer matrix formulation was evaluated for primary skin irritation in accordance with the guidelines of ISO 10993-10, Biological evaluation of medical devices ¨ Part 10: Tests for irritation and skin sensitization.
[0085] Two 0.5 mL portions of the test article and control article (namely, saline solution, i.e., 0.9% Sodium chloride solution) were topically applied to the skin of each of three rabbits and left in place for 24 hours. The sites were graded for erythema and edema at 1, 24, 48 and 72 hours after removal of the single sample application.
[0086] There was no erythema and no edema observed on the skin of the animals treated with the test article. The Primary Irritation Index for the test article was calculated to be 0Ø The response of the test article was categorized as negligible.
Example 2: Guinea pig Maximization Sensitization Test [0087] The test article was evaluated for the potential to cause delayed dermal contact sensitization in a guinea pig maximization test. This study was conducted based on the requirements of ISO 10993-10, Biological evaluation of medical devices ¨ Part 10: Tests for irritation and skin sensitization.
Dose determination was performed to determine a suitable test article concentration for testing. The test article solution was intradermally injected and occlusively patched to ten test guinea pigs. The control article was similarly injected and occlusively patched to five control guinea pigs. Following a recovery period, the test and control animals received challenge patches of the test solution and the vehicle control article. All sites were scored for dermal reactions at 24 and 48 hours after patch removal.
[0088] The test article solution showed no evidence of causing delayed dermal contact sensitization in the guinea pig. The test article was not considered a sensitizer in the guinea pig maximization test.
Example 3: Cytotoxicity Test [0089] The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e. less cytotoxic) as compared to the previous known Ionic Polymer Matrix (IPM) Wound Gel. The details of the test performed is provided below:
[00901 The test article was evaluated to determine the potential for cytotoxicity based on the requirements 9f ISO 10993-5: Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity. Triplicate wells were dosed with 0.1 mL of the test article placed on a filter (test filter disc).
Triplicate wells were dosed with 0.1 mL of 0.9% sodium chloride solution placed on a filter disc (filter disc control). Triplicate wells were dosed with a 1 cm length portion of high density polyethylene as a negative control.
[0091] Triplicate wells were dosed with a 1 cm x 1 cm portion of latex as a positive control. Each was placed on an agarose surface directly overlaying a sub confluent monolayer of L-929 mouse fibroblast cells. After incubating at 37 C in the presence of 5% CO2 for 24 hours, the cultures were examined macroscopically and microscopically for any abnormal cell morphology and cell lysis.
[0092] The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e., less cytotoxic) as compared to the previously known Ionic Polymer Matrix (IPM) Wound Gel, as shown in Table below.
Zone of lysis (mm) Test article IPM Wound Gel Test Disc I 1 4 Test Disc 2 1 4 Test Disc 2 1 4 Example 4: Stability of Bio-fermented Sodium Hyaluronate Polymer Matrix Formulation 100931 Stability of the test article was studied after incubation at various temperatures and time-intervals.
100941 Methods: The concentrations of sodium hyaluronate were measured after incubation periods of various lengths. Other test parameters included appearance test, methylparaben assay, pH and viscosity.
[0095] Results: Examples of test results are shown in Table # 1. All concentrations of sodium hyaluronate are in % w/w.
Temperature Sodium hyaluronate % (w/w) Month 0 Month 3 Month 6*
25 C and 60%RH 2.48 2.51 2.52 30 C and 65%RH 2.48 Not Scheduled 2.53 30 C and 75%RH 2.48 2.47** 2.55 40 C and 75%RH 2.48 2.52 2.46 *It has been seen that the response factor of the calibration curve increase during the stability study. This is probably due to absorption of water for the standard.
The response factor has increased to 104% from the zero value to the six months value (103% from zero to three months). The results are therefore false higher.
**% RSD for 2 in weights (4 injections) 4.25%.
All other test parameters were all well within the stability test limits.
[0096] Conclusions: It can be concluded from the results presented above that the test article is stable over a prolonged period as substantiated by the results from the accelerated stability tests at 40 C and 75%RH.
Example 5: Method validation of determination of sodium hyaluronate content in the test article [0097] An HPLC method was validated for the determination sodium hyaluronate in the test article was developed. An HPLC System with a UV
detector was used.
[0098] Results and Discussion: The average assay obtained for sodium hyaluronate in the test article was 2.545 % w/w and the % relative standard deviation was 0.32. Over a range of 1.14% (or 114 g/mL) to 3.99% (or 399 ps/mL) the assay showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.481 for the % Label claim of sodium hyaluronate. Hence the HPLC method used for the determination of sodium hyaluronate content (or assay) has been validated and verified.
Example 6: Method validation for the determination of methylparaben content in the test article [0099] An HPLC method was validated for the determination methylparaben content in the test article was developed. An HPLC System with a UV detector was used.
[00100] Results and Discussion: The average assay obtained for methylparaben was 103.3% and the % relative standard deviation was 0.56. Over a range of 0.06% to 0.18% the assay of methylparaben showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.096 for the Label claim of methylparaben. Hence the HPLC method used for the determination of methylparaben content (or assay) has been validated and verified.
Example 7: Antimicrobial Effectiveness Testing (AET) [001011 Antimicrobial efficacy testing (AET) measures the effectiveness of antimicrobial preservatives that are. added to inhibit the growth of microorganisms that may be introduced inadvertently during the manufacturing process or during product use. Antimicrobial effectiveness testing should be performed, on all aqueous-based products that are injectable, ophthalmic, otic, nasal, oral, and topical.
[00102] The antimicrobial preservative in the test article is methylparaben at target concentration of 0.2% w/w.
1001031 Methods: The AET was performed on the test article as per USP<51>
compendial standard using the all five microorganisms ¨ Escherichia coli (fermentative gram negative bacteria), Pseudomonas aeruginosa (non-fermentative gram negative bacteria), Staphylococcus aureus(gram positive bacteria), Aspergillus niger (mold or fungus) and Candida albicans (yeast).
The Antimicrobial Effectiveness Testing was performed on three lots at 18 months' time-point Long-Term Stability Study.
[00104] Results: The test results indicated that the proposed preservative system and concentration met the preservative effectiveness test requirements for Category 2 products (as per USP, topically used products made with aqueous bases or vehicles, non-sterile nasal products, and emulsions, including those applied to mucous membranes).
[00105] Conclusion: The preservative system has been demonstrated to be suitable and effective in protecting the test article from microbial growth or from inadvertently introduced microorganisms.
Example 8: Closure of incision lines in patients with digit amputations [00106] Study design: IMP Wound Gel Bio was used in the healing of incision lines after digit amputations. Over a period of 9 months, 116 amputations were performed on diabetic patients with non-healing, digital diabetic ulceration. Blood supply was never perfect in those patients, however, is also not profoundly impaired. The treatment protocol was to apply a thin film of IPM Wound Gel Bio along the incision line, on a daily basis, with the wound site covered with foam dressing. The patients were seen 1 week postoperatively and again 2 weeks later.
[00107] Results: The results that 94 (81%) of those patients healed, with complete epithelialization of the incision line within 1-2 weeks. This is in contrast to a typical 4 week healing time that was observed prior to using IPM
Wound Gel Bio. In addition, the complication rate was correspondingly low as there was no incision line dehiscence or infection.
1001081 Conclusions: The overall experience with IPM Wound Gel Bio has been extremely positive. Particularly striking was the consistency in the healing times of the incision lines, given that the patients were very sick patients with profound underlying end organ damage. The healing mechanism in these individuals is grossly impaired and amputation with primary closure is frequently fraught with postoperative complications. The rate of these complications was reduced with the introduction of IPM Wound Gel Bio as a postoperative treatment protocol and as such the need for ongoing homecare was reduced as well the patient's return to work or normal activities of daily living was accelerated.
Example 9: A formulation containing sodium hyaluronate for application to wounds Table 3. A preferred biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate Ingredient Amounts (% w/w) Sodium hyaluronate 2.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit [00109] The above batch contained a sodium hyaluronate as a humectant and matrix forming agent, hydroxyethylcellulose is a thickening agent and helps in forming polymer matrix, polyethylene glycol is a solvent, methylparaben as preservative and water as a solvent. Several experiments were done and the optimum pH range was established to be 5.0 to 7Ø The optimum viscosity range of the solution was established to be in the range of 10,000 ¨ 50,000 cps. The product is found to be stable.
100110] The formulation in Table 1 was prepared by adding methylparaben to water in a suitable container and mixing at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate (having a molecular weight from 600,000 ¨ 800,000 Daltons) in a steady flow to the mixture gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour). Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
1001111 In a separate container dissolve 1% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours).
[00112] The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed followed by low speed for long period (about 4 hours) until a homogenous solution is produced.
[00113] Add polyethylene glycol into the mixture while mixing at a medium speed. Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed for a few hours (minimum of about 3 hours).
The bulk gel is then filled in tubes or bottles and capped.
Example 10: A formulation containing sodium hyaluronate and pantothenic acid for topical use [00114] A formulation containing sodium hyaluronate and pantothenic acid may be used in the treatment of damaged skin and can be used in the treatment of atopic dermatitis.
Table 4. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and pantothenic acid.
Ingredient Amounts (/0 w/w) Sodium hyaluronate 1.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Ingredient Amounts CAD w/w) Pantothenic acid (Vitamin B5) 1.5 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit 1001151 The formulation in Table 2 was prepared as detailed below:
First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the dissolvent thickens and the spin stays while charging sodium hyaluronate in a suitable container. Mix for few hours (about 2 hours) at medium speed.
Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[00116] In a separate container dissolve 1.0% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for a few hours (from about 1 to about 2 hours).
[00117] Next the hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed until a homogenous solution is produced. The resulting solution is mixed at medium speed for long period (overnight, or about 8 hours to about 15 hours) until a homogenous solution is produced. Add polyethylene glycol into the mixture while mixing at a medium speed for about 1 hour. This is followed by the addition of pantothenic acid and mixing well at medium speed for few hours (about 2 hours) until dissolved and the gel is homogeneous. The bulk gel is then filled in tubes or bottles and capped.
Example 11: A formulation containing sodium hyaluronate and diclofenac sodium for topical use [00118] A formulation containing sodium hyaluronate and diclofenac sodium can be used to treat actinic keratosis and in the relief of musculoskeletal pain in areas affected by the pain. Such areas include, but are not limited to, knees, ankles, feet, back, neck, elbows and hips.
Table 5. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and dicloflenac sodium. The formulation was found to be stable.
Ingredient Amounts (% w/w) Dicloflenac sodium 3 Sodium hyaluronate 2.3 Hydroxyethylcellulose 0.7 Methoxypolyethylene glycol 10 Methylparaben 0.3 Water q.s.*
Total 100 = quantum sufficit [00119] The formulation in Table 3 was prepared as follows:
First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate to it while gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous.
[00120] In a separate container dissolve 0.7% hydroxyethylcellulose in purified water while stirring at low to medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours).
[00121] The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed for a long period (from about to about 15 hours) until a homogenous solution is produced.
[00122] Add methoxypolyethylene glycol (MPEG) 10% into the mixture. The mixing speed should be increased for the mixture while this step is being performed to a high speed. The resulting mixture thus formed should be allowed to mix at medium speed for a few hours (from about 3 to about 4 hours).
1001231 Using safe techniques, 3% diclofenac sodium should be slowly added to the mixture. Again the mixing speed for the purpose of addition of diclofenac should be increased to high speed, and the addition of entire quantity of diclofenac should be completed within a short duration (about 15 minutes).
1001241 The final- mixture is clear with a slight green tint following further mixing for long duration (about 15 to about 20 hours) at medium speed. The final product should be transferred, using aseptic technique, to a bulk storage container and then the bulk gel is filled in tubes or bottles and capped.
Example 12: A formulation containing sodium hyaluronate for treating vaginal dryness containing using niacin and glycerin Table 6. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate And niacin and glycerin.
Ingredient Amounts (% w/w) Niacin 0.85 Ingredient Amounts (% w/w) Glycerin 3 Sodium hyaluronate 1.5 Hydroxyethylcellulose 0.7 Polyethylene glycol 3 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit ** Glycerin USP should be used Not More Than 0.10% each for diethylene glycol and ethylene glycol is found in Glycerin as per USP]
[00125] A transdermal preparation of niacin (0.85%) and glycerin (3%) formula for Table 4 is prepared in the following manner. First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous.
[00126] Next, a solution is prepared by adding 0.7% HEC to purified water while stirring at low to medium speed and mixing well. Continue stirring for few hours (from about 1 to about 2 hours). The resulting solution is then added to the above formed mixture of sodium hyaluronate and mixed at medium speed for a long period (overnight, or about 8 hours to about 15 hours) to form a sodium hyaluronate/HEC polymer matrix.
[00127] To the resulting mixture PEG is added and stirred at medium speed for a few hours (about 2.5 hours).
[00128] Then, niacin and glycerin is added to the HA/HEC polymer matrix. The mixture is stirred at low speed for few hours (about 2 hours). The bulk gel is either stored for filling or a 0.5 to 0.75 ml of the resulting gel is loaded into syringes and stored in a refrigerator.
Example 13: Test method for determination of sodium hyaluronate [00129] An HPLC test method for the determination of sodium hyaluronate in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed.
Column BioSep SEC-s2000, 300 mm x 7.8 mm, 5pt Detection UV @205 nm Column Temp.: 40 C
Injection Volume: 10 piL
Flow Rate: 1.3 mUmin Run Time: 20 min Mobile Phase: 50 mM KH2PO4, pH adjusted to 7.0 [00130] The assay is based on HPLC analysis with a size exclusion analytical column and UV detection at 205 nm.
Example 14: Test method for determination of methylparaben [00131] An HPLC test method for the determination of methylparaben in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed.
Column Kinetex, C8, 100 mm x 4.6 mm, 2:6 t, 100 A
Detection UV g254 nm Column Temp.: 35 C
Injection Volume: 20 !IL
Flow Rate: 1.4 mL per min Run Time: 2 min Mobile Phase: 60:40 (v/v) 0.1% TFA in Milli-Q Water;
0.1% TFA in Acetonitrile 1001321 The assay is based on HPLC analysis with reverse phase C8 analytical column and UV detection at 254 nm.
1001331 Although specific embodiments of the invention have been described, it will be apparent to one skilled in the art that variations and modifications to the embodiments may be made within the scope of the following claims.
Example 15: Pharmacokinetics and Bioavailability of 3% Diclofenac IPM
Matrix 2.3 % Sodium Hyaluronate Gel [00134] An open label, single centre, single dose, single dose, one-treatment, one period, pharmacokinetic and bioavailability study was carried out. Six normal, healthy, non-smoking males between the ages of 18-45 were administered 3% diclofenac IPM matrix gel made with 2.3% avian sodium hyalorunate, which was applied once for a 24 hour period. A total of 4 cc was the applied to the anterior right knee of each subject. Pharmacokinetics and bioavailability of the single dose application was assessed. A total 18 blood samples and 8 urine samples were collected for each subject during the 24 hour period after administration. The concentration of diclofenac was assessed for each sample. Diclofenac plasma and urine concentrations are presented in Table 7 and 8. Diclofenac was found in samples from all subjects. Concentrations varied from subject to subject, but this was normal for diclofenac.
Table 7. Diclofenac Plasma Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Subject Hour Min Diclofenac Concentration Found Ing/m11 Subject Hour Min Diclofenac Concentration Found [ng/m11 1 1 0 0.074 1 1 5 0.228 1 2 0 0.385 1 2 5 0.487 1 3 0 0.655 1 3 5 0.859 1 4 0 0.807 1 5 0 0.944 1 6 0 1.40 1 7 0 1.53 1 8 0 1.75 1 12 0 1.57 1 16 0 1.93 1 24 0 2.33 2 1 0 0.042 2 1 5 0.191 2 2 0 0.369 2 2 5 0.403 2 3 0 0.471 2 3 5 0.410 2 4 0 0.496 2 5 0 0.814 2 6 0 1.03 2 7 ________ 0 1.01 2 8 0 1.33 2 12 0 1.25 2 16 0 1.98 2 24 0 2.44 3 2 0 0.049 3 2 5 0.184 3 3 0 0.118 3 3 5 0.184 3 4 0 0.232 3 5 0 0.244 3 6 0 0.377 3 7 0 0.489 , Subject Hour Min Diclofenac Concentration Found ing/mij 3 8 0 0.532 3 12 0 0.944 3 16 0 1.64 3 24 0 2.92 4 2 5 0.090 4 3 5 0.053 4 4 0 0.045 4 5 0 0.084 4 6 0 0.107 4 7 0 0.312 4 8 0 0.383 4 12 0 0.563 4 16 0 0.940 4 24 0 0.429
6120,804, U.S. Pat. 6,387,407, and U.S. Pat. 6,723,345. HA polymer matrices formulated with other active ingredients are also known to be useful as formulations for sustained release of the pharmaceutical agents. HA polymer matrix formulations for sustained release delivery of active ingredients are disclosed in U.S. Pat. 6,063,405, U.S. Pat. 6,335,035, and U.S. Pat.
6,007,843.
100051 Preparing sodium hyaluronate polymer matrix formulations presents many challenges. Initially, in the 1980s only HA obtained from animal sources was available commercially, and many of the formulations were delivered by injection, or used as drops in the eye, rather than for topical use for dermatological conditions. The natural HA used in various formulations has usually been obtained from rooster combs. The rooster comb (also known as a chicken comb) is an avian source and as such is of animal origin. As a result, sodium hyaluronate formulations manufactured using sodium hyaluronate from rooster combs have been known to cause allergies and carry other risks associated with products of animal origin, namely a risk of transmission of animal diseases to humans. Consequently, the currently approved topical products containing sodium hyaluronate formulations available on the market are contra-indicated for those patients who are hypersensitive to sodium hyaluronate of animal origin.
100061 Moreover, sodium hyaluronate is difficult to formulate in high concentrations above 1.5% w/w, due to the difficulty in manufacturing a formulation that maintains stability and is not too viscous for normal use when packaged in a tube. For this reason many of the commercial formulations on the market have a concentration of HA or sodium hyaluronate well below 1%
w/w, and many in fact have a concentration at around 0.2% w/w. To the inventors' knowledge, there are no products currently on the market that contain more than 1.5% w/w sodium hyaluronate. When not mixed and manufactured properly, a high HA or sodium hyaluronate concentration formulation will quickly break down, and therefore the percentage of HA or sodium hyaluronate in the formulation will fall below the acceptable limit (+/-10% of original amount), resulting in a very short shelf life for the product.
Formulations containing a high concentration of sodium hyaluronate therefore present a challenge due to the instability of the matrix. This results in inconsistencies in the matrix formulation and impairs the ability of sodium hyaluronate formulations to perform their functions. For example, when applied to wounds to promote healing, a sodium hyaluronate polymer matrix formulation helps to maintain a moist wound environment, an effect that is dependent on the formulation maintaining its high level of sodium hyaluronate concentration. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing. However, due to their instability and the resulting drop in the level of sodium hyaluronate that occurs as the formulation breaks down, high concentration sodium hyaluronate formulations are not effective in maintaining a moist environment. When formulated for the delivery of a drug, the inconsistency of high concentration sodium hyaluronate formulations reduces the ability of such formulations to allow the drug to diffuse through the tissue when administered, thereby impairing their ability to achieve the therapeutic dose.
100071 In addition, the sodium hyaluronate polymer matrix formulation product formerly marketed under the name of Ionic Polymer Matrix (IPM) Wound Gel was withdrawn from the market due to problems with the formulation.
[0008] Therefore, a need exists for a method for formulating a sodium hyaluronate polymer matrix containing a high concentration of sodium hyaluronate that can be manufactured and sold commercially.
SUMMARY OF THE INVENTION
[0009] The present invention relates to stable polymer matrix compositions comprising a high concentration (about 1.5% to about 3.5% w/w) of sodium hyaluronate obtained from a bacterial Streptococcus zooepidemicus or Bacillus subtilis source (bio-fermented sodium hyaluronate), a non-ionic polymer, said polymer matrix compositions further comprising polyethylene glycol and methylparaben.
[0010] In one aspect of the present invention, the polymer matrix compositions of the present invention comprise components which are of compendial (USP
or Ph. Eur.) and/or of pharmaceutical grade. In a further aspect of the invention, the polymer matrix compositions comprise components of certain specifications.
100111 In one aspect, polymer matrix compositions of the present invention may be used in the treatment of wounds, burns, and certain dermatological conditions.
[0012] In another aspect of the present invention, the polymer matrix compositions comprise an active ingredient. In this aspect of the invention, the polymer matrix compositions may be used for trans-dermal delivery, topical, and sustained release delivery of the active ingredient.
[0013] In some aspects, the polymer matrix compositions may be used for the treatment of musculoskeletal pain. A further aspect of the present invention relates to the use of the polymer matrix compositions in the treatment of vaginal dryness.
[0014] In a further aspect, the present invention relates to methods for preparing stable polymer matrix compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The inventors determined that the product IPM Wound Gel could not be successfully formulated because the product was made from naturally sourced sodium hyaluronate ("natural sodium hyaluronate") and because the testing regimen was not sufficient and raw materials were not of sufficient quality. The natural sodium hyaluronate was produced from rooster combs (which is an animal origin source) and was of cosmetic grade. The natural sodium hyaluronate was found to be more prone to microbiological contamination including that from the manufacturing facility and surrounding environment. This led to microbiological failure of the product rendering the product unsafe and not useful. Moreover, the product IPM Wound Gel used ingredients that were of insufficient or inconsistent grade. Also, testing to determine the quality of the IPM Wound Gel Product was insufficient to ensure a stable product of sufficient quality.
[0016] The inventors unexpectedly discovered that sodium hyaluronate polymer matrix compositions can be advantageously formulated using bio-fermented sodium hyaluronate obtained from strains of Streptococcus zooepidemictts or Bacillus subtilis bacteria (herein referred to as "bio-fermented sodium hyaluronate").
[0017] The inventors further determined that sodium hyaluronate polymer matrix compositions can be advantageously formulated by using ingredients of sufficient quality, i.e., ingredients of compendia! (USP or Ph. Eur.) and/or pharmaceutical quality, including bio-fermented sodium hyaluronate, and through the use of validated assays methods for testing the amount of sodium hyaluronate and methylparaben in the formulation, as well as through compliance with Bacterial Endotoxin Test ("BET"), and microbiological test limits, including for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella sp., as well as compliance with other parameters.
[0018] The inventors further developed a process for formulating a polymer matrix composition containing a high concentration (i.e., between about 1.5%
w/w to about 3.5% w/w) of sodium hyaluronate and produced a stable polymer matrix composition containing a high concentration of sodium hyaluronate.
[0019] Sodium hyaluronate (CAS Number: 9067-32-7, molecular formula [C14H20N1 'Nab) consists of a linear polysaccharide, whose basic unit is a disaccharide of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic (1-3) bond. The disaccharides units are linearly polymerized by hexosaminidic (1-4) linkages, as shown in Formula 1:
[0020]
coAki 01:00,110) õ0 OH
[0021] Sodium hyaluronate is a white or almost white, very hygroscopic powder or fibrous aggregate. It is odorless and the pH of the 5% solution is in the range of 5.0¨ 8.5. Sodium hyaluronate is easily soluble in cold water and insoluble in organic solvents. Sodium hyaluronate of high quality, i.e., BET
<0.5 EU/g microbial qualit., may be obtained from commercial suppliers.
100221 The process of obtaining bio-fermented sodium hyaluronate can vary, but in general, the preparation involves the following steps: fermenting selected Streptococcus zooepidemicus bacterial strains; selecting the sodium hyaluronate crude product obtained from fermentation; purifying the crude product by filtration; precipitating sodium hyaluronate with an organic solvent; and drying. Bio-fermented sodium hyaluronate obtained from Streptococcus zoopidemicu,; is available commercially from suppliers such as QUFU, Freda, and Contipro.
100231 As an example, U.S. Pat. No. 4,517,295 to Bracke et al. discloses the preparation of hyaluronic acid in high yield from Streptococcus bacteria by fermenting the bacteria under anaerobic conditions in a CO2 enriched growth medium, separating the bacteria from the resulting broth and isolating the hyaluronic acid from the remaining constituents of the broth. Separation of the microorganisms from the hyaluronic acid is facilitated by killing the bacteria with trichloroacetic acid. After the removal of the bacteria cells and concentration of the higher molecular weight fermentation products, the hyaluronic acid is isolated and purified by precipitation, re-suspension and re-precipitation.
100241 One particular fraction of bio-fermented sodium hyaluronate that exhibits excellent matrix formation according to the present invention is sodium hyaluronate having an average molecular weight between about 600,000 Daltons to abOut 800,000 Daltons. Bio-fermented sodium hyaluronate having an average molecular weight of 500,000 to 1,000,000 Daltons has also been found to be acceptable in the formulations of the present invention.
100251 In addition to bio-fermented sodium hyaluronate, polymer matrix formulations of the present invention include a non-ionic polymer. Non-ionic polymers suitable for use in formulations of the present invention include polyvinylpyrrolidones, poloxamers, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymers, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymers, polyacrylamides, polyethylene oxide copolymers, neutralized polyacrylic acids, polysorbates, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) and alpha, omega-dialkyl-ethoxylates, or mixtures thereof.
[0026] Polyvinylpyrrolidones suitable for use with the present invention include PVP K-90, PVP K-17, and polyvinyl pyrrolidone-vinyl acetate (PVP-VA) copolymer.
[0027] Cellulose derivatives-suitable for use with the present invention include hydroxyethylcellulose, hydroxypropylmethylcellulose, ethyl(hydroxyethyl)cellulose, and methyl cellulose.
[0028] Sorbitol based polymers suitable for use with the present invention include Neosorb.
[0029] Polyacrylic acids suitable for use with the present invention include neutralized Carbopol 980 and Carbopol 940.
[0030] Polysorbates suitable for use with the present invention include Polysorbate 20 (USP/Ph. Eur.), Polysorbate 21, Polysorbate 40 (USP/Ph.
Eur.), Polysorbate 60 (USP/Ph. Eur.), Polysorbate 61, Polysorbate 65, Polysorbate 80 (USP/Ph Eur.), Polysorbate 81, Polysorbate 85, and Polysorbate 120.
[0031] Hydroxyethylcellulose ("HEC") is a particularly preferred non-ionic polymer for use with the present invention.
[0032] It is believed that there are many such non-ionic polymers that can be used to successfully form the polymer matrix formulations of the present invention. As such, included in the present invention are any non-ionic polymers that can successfully form a polymer matrix with sodium hyaluronate.
[0033] Other suitable ingredients for use in the manufacture of the polymer matrix compositions of the present invention include stabilizers and fillers such as methylparaben, benzyl alcohol, polyethylene glycol, methoxypolyethylene glycol, and purified water. Preferably, ingredients used in the bio-fermented sodium hyaluronate polymer matrix compositions of the present invention conform to the compendial standards (USP or Ph. Eur.) [0034] When compared to the product IPM Wound Gel, the bio-fermented sodium hyaluronate used in the preferred embodiment of compositions of the present invention is of compendial or pharmaceutical grade quality. All raw material used in the formulations of the present invention are of better microbiological quality and all are of compendial and/or pharmaceutical grade. The following Table 1 compares the changes made in specifications of raw materials from the formulation used in the product IPM Wound Gel to the formulation of the present invention.
Table 1. Changes to specification.; of raw materials used in the formulation of the present invention in comparison to those used in the product IPM Wound Gel.
Sodium hyaluronate bio-fermented 1PM Wound Gel formulation of the present invention Sodium hyaluronate Grade: Cosmetic grade Grade: Pharmaceutical grade (Ph.
Eur.) Nucleic acid: <0.5% (Ph. Eur.) Protein content < 5% Protein content < 0.3% (Ph. Eur.) TYMC < 50 cfu (colony forming units)/g TYMC < 10 cfu/g (Ph. Eur.) E.coli : Negative Staphylococcus aureus: Absence (Ph.
Eur.) Pseudomonas aeruginosa: Absence (Ph.
Eur.) Escherichia coli: Absence (Ph. Eur.) Salmonella sp.: Absence (Ph. Eur.) Bacterial Endotoxin Test (BET) < 0.5 IU/mg Hydroxyethylcellulose (HEC) Sodium hyaluronate bio-fermented 1PM Wound Gel formulation of the present invention TAMC (Total Aerobic Microbial Count) TAMC < 100 cfu/g (USP/Ph. Eur.) <1000 cfu/g Polyethylene Glycol 200 (PEG 200) PEG 200 or PEG 400 PEG 200 Limit of ethylene glycol and diethylene glycol (combined): < 0.25% w/w (USP) TAMC < 100 cfu/mL (USP) TYMC < 10 cfu/mL (USP) Methylparaben TAMC < 100 cfu/mL (USP/Ph. Eur.) TYMC < 10 cfu/mL (USP/Ph. Eur.) Purified water TAMC < 100 cfu/mL (USP/Ph. Eur.) BET < 0.25 EU/mL (USP/Ph. Eur.) [0035] The grade of PEG used with IPM Wound Gel was intermittently PEG
400 which led to failure of product due to instability. The matrix formed were not stable. The PEG used with the preferred embodiment of formulations of the present invention is of better purity in that the restricted substances, namely, ethylene glycol and diethylene glycol are well controlled.
[0036] Sodium hyaluronate used with the IPM Wound Gel was of cosmetic grade. In the preferred embodiment, the present invention uses sodium hyaluronate of pharmaceutical grade with consistent quality and content of nucleic acid and protein. In the preferred embodiment of the present invention, the TYMC microbial count is better controlled, and all the specified microorganisms are tested for their absence. Additionally, in the preferred embodiment of the present invention, BET is tested, and the protein content of sodium hyaluronate has been significantly reduced (from 5% limit for IPM
Wound Gel to 0.3% limit for the preferred embodiment of the present invention).
[0037] In regard to HEC used in the preferred embodiment of the present invention, there is a better control of microbial count (<100 cfu/g) than with the HEC used with IPM Wound Gel (<1000 cfu/g) provided by the raw material supplier, and the hence the formulation of the present invention in the preferred embodiment was found to be significantly better quality.
[0038] In the preferred embodiment of the present invention, methylparaben raw material is tested for TAMC and TYMC tests to ensure that only good quality raw material is used in the manufacture of the formulation in the preferred embodiment of the present invention.
[0039] Additionally, in the preferred embodiment of the present invention, purified water is better controlled microbiologically by performing additional tests TAMC and BET.
[0040] The bio-fermented sodium hyaluronate polymer matrix formulation is a clear viscous, odorless, aqueous gel composed principally of sodium hyaluronate, a derivative salt of hyaluronic acid. The formulation of bio-fermented sodium hyaluronate is a polymer matrix made up of negatively charged polymer, namely, sodium hyaluronate, and a non-ionic polymer, such as HEC. In other words, sodium hyaluronate (as a negatively charged polymer) forms part of the polymer matrix in combination with a non-ionic polymer, such as HEC, and it helps to maintain the moist environment through the matrix.
[0041] The concentration of sodium hyaluronate in the polymer matrix is from about 1.5% to about 3.5% w/w, and the concentration of the non-ionic polymer, other than HEC, is from about 0.1% w/w to about 2.0% w/w, preferably from about 0.7% w/w to about 1.3% w/w. The concentration of HEC is from about 0.1% w/w to about 1.5% w/w, preferably from about 0.7%
w/w to about 1.3% w/w.
[0042] Preferably, non-ionic polymers such as HEC are of compendial or pharmaceutical grade. Where non-ionic polymers are not available in compendial or pharmaceutical grade, non-ionic polymers of best available quality should be used.
[0043] The viscosity of bio-fermented sodium hyaluronate polymer matrix formulation should be in the acceptable limits or range so that the matrix is stable and is easy to apply on the skin, wound, or other tissue. The formulation should also have a viscosity that can be handled easily during manufacturing and filling. The viscosity range has been investigated. It was determined that the formulation of the present invention should have a viscosity of about 10,000 to 50,000 cps (cP) when tested at room temperature. The therapeutically useful pH range of the formulation was set at 5.0 to 7Ø
[0044] Preferably, the bio-fermented sodium hyaluronate polymer matrix formulation comprises sodium hyaluronate (2.5%, w/w), HEC (1% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w). The test results found that the average viscosity of this bio-fermented sodium hyaluronate formulation is 30,000 cps, i.e. exactly in the middle of the range (10,000 ¨ 50,000 cps). It is well known that molecular weight of sodium hyaluronate and concentration of sodium hyaluronate have a direct effect on the viscosity of the product.
[0045] The solutions used to prepare the gels of the present invention may be prepared in a variety of ways. The non-ionic polymer such as HEC may be dissolved in water, mixed with anionic or negatively charged sodium hyaluronate solution to form the sodium hyaluronate/non-ionic polymer matrix, and then the optional active ingredient may be added or loaded to the system.
[0046] The preparation procedure may involve dissolving a non-ionic polymer such as HEC in water at a low to medium speed for few hours (about 1 to about 2 hours).
[0047] Separately, sodium hyaluronate may be slowly added to water while stirring at high speed, followed by stirring at medium speed for few hours (about 2 hours), followed by stirring at low speed for a long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[0048] The non-ionic polymer such as HEC solution may be added to the sodium hyaluronate solution and mixed at medium speed followed by mixing at low to medium speed for long period (from about 4 hours to about 15 hours) until a homogenous solution is produced.
[0049] Conventional pharmaceutically acceptable emulsifiers, suspending agents, solvents (such as polyethylene glycol 200), antioxidants (such as sodium meta-bisulfate) and preservatives (such as benzyl alcohol, methylparaben) may then be added to this system.
[0050] When formulated with an active ingredient as a system for transdermal or sustained release of the active ingredient, using safe techniques, the active ingredient (e.g., 3% diclofenac sodium) may be slowly added to the above sodium hyaluronate/non-ionic polymer matrix mixture while increasing the speed to high speed, and the addition of the entire quantity of the active ingredient should be completed within a short duration (about 15 minutes).
[0051] Once all the components are blended together, such as by mixing at low to medium speed for from about 2 hours to about 20 hours, the system is filled into tubes. The resulting system is clear to slightly hazy, colourless, viscous, odorless gel which are found to be stable on storage for a few years (from 18 months to 4 years).
[0052] Preferably, a bio-fermented sodium hyaluronate polymer matrix formulation is prepared as follows. First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours).
Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate in a steady flow to the mixture gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour).
Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyaluronate =
polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[0053] In a separate container dissolve 1% HEC in purified water while stirring at medium speed and mix well. Continue stirring for a few hours (from about 1 to about 2 hours).
[0054] The resulting HEC solution is added to the sodium hyaluronate solution and mixed at medium speed followed by low speed for a long period (about 4 hours) until a homogenous solution is produced.
[0055] Add polyethylene glycol into the mixture while mixing at a medium speed. Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed for a few hours (minimum of about 3 hours).
The bulk gel is then filled in tubes or bottles and capped.
[0056] The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of pharmaceutical compositions, medical device compositions, natural health product compositions, and dietary supplement compositions. In topical applications, the polymer matrix compositions of the present invention serve to maintain moist wound environment. The maintenance of a moist wound environment is widely recognized to positively contribute to wound healing process and relief from certain dermatological conditions. The polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be used for topical application in the treatment of many types of ulcers (wounds), including venous stasis, diabetic wounds, and post-operative incisions, and in anti-aging treatments. The invention has shown to be especially effective in hard-to-heal wounds.
100571 More particularly, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown to be useful in topical applications for the management of minor burns (1' degree burns), minor abrasions, minor cuts, and in helping to relieve dry waxy skin irritations association with dry skin conditions. Furthermore, the polymer matrix compositions formulated in with bio-fermented hyaluronate of the present invention have been shown be useful in topical applications for the management of exudating wounds such as leg ulcers, pressure ulcers, diabetic ulcers, surgical wounds (post-operative and donor sites), mechanically or surgically debrided wounds, second degree burns, and the management and relief of burning, itching and pain associated with various types of dermatoses, including atopic dermatitis, allergic contact dermatitis, and radio-dermatitis.
[0058] In other aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention may be also used in the manufacture of a system for a sustained release delivery of an active ingredient, and in the manufacture of a system for transdermal delivery of an active ingredient.
[0059] In additional aspects, the polymer matrix compositions formulated with bio-fermented sodium hyaluronate of the present invention can be used in the manufacture of personal lubricants for use in the management of symptoms of female sexual dysfunction.
[0060] When formulated with an active ingredient as a system for transdermal delivery of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation is believed to form a matrix which microencapsulates, suspends, and/or entraps the active ingredient such that when it is administered, it is slowly released into the systemic circulatory system or muscular tissue providing a method of delivering an active ingredient to an affected site in the body through the skin.
[0061] The active ingredient may be added either directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC
or it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC and mixed well. The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be ,..dded to this system. One particularly non-limiting effective material for solubilizing water insoluble drugs is methoxypolyethylene glycol (MPEG). Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, if required, and stored for future use.
[0062] The formulations of this invention formulated with an active ingredient for trans-dermal delivery of an active ingredient may potentially be used to treat a variety of mammal and animal conditions and physical states. These systems may .have a particular application to pain management, namely the treatment and alleviation of pain associated with any disease, condition or physical state.
[0063] Without being limited to the specific pain being treated, the preparations of this invention formulated with an active ingredient for transdermal delivery may treat the following non-limiting locations or sources of pain below the dermal level of the skin, including, but not limited to knees, ankles, hands, feet and neck.
[0064] In addition to treating disorders associated with pain below the dermal level of the skin, the preparations of this invention formulated with an active ingredient for transdermal delivery may be used to treat a wide variety of dermatologic disorders as well as many types of ulcers (wounds) including venous stasis and diabetic wounds. The invention has shown to be especially effective in hard to heal wounds. Exemplary, non-limiting disorders that may potentially be treated with the preparations of this invention formulated with an active ingredient for transdermal delivery include dermatitis conditions such as: Contact Dermatitis; Atopic Dermatitis; Radio Dermatitis; Seborrheic Dermatitis; Nummular Dermatitis; Chronic Dermatitis of Hands and Feet;
Generalized Exfoliative Dermatitis; Stasis Dermatitis; and Localized Scratch Dermatitis; bacterial infections of the skin, such as: Staphylococcal Diseases of the Skin, Staphylococcal Scalded Skin Syndrome; Erysipelas; Folliculitis;
Furuncles; Carbuncles; Hidradenitis Suppurativa; Paronychial Infections and Erythrasma; superficial fungal infections such as: Dermatophyte Infections;
Yeast Infections; Candidiasis; and Tinea Versicolor; parasitic infections of the skin such as: Scabies; Pediculosis; and Creeping Eruption; disorders of hair follicles and sebaceous glands such as: Acne; Rosacea; Perioral Dermatitis;
Hypertrichosis; Alopecia; Pseudofolliculitis Barbae; and Keratinous Cyst;
scaling papular diseases, such as: Psoriasis; Pityriasis Rosea; and Lichen Planus; pressure sores; benign tumors and malignant tumors.
[0065] A wide variety of active ingredients which may be administered topically may be used in the transdermal delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including benzocaine, tetracaine, mepivacaine, prilocaine, etidocaine, bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat.
No. 3,652,762), phenacetin and salicylamide; nonsteroidal anti-inflammatories (NSAIDS) selected from the group consisting of naproxen, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, phenacetin, salicylamide, and indomethacin; antibiotics including amebicides, broad and medium spectrum, fungal medications, monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa;
metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatis-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex including vitamin B5 and B3 (Niacin), vitamin C, vitamin B12 and folic acid and veterinary formulations.
100661 Doses may vary from patient to patient depending on the type and severity of the condition being treated and the active ingredient being administered. Generally, doses of 1 ml to 75 ml may be administered with preferred doses using 2 to 25 ml of the gelled matrix system.
[0067] When formulated with another active ingredient as a system for sustained release of an active ingredient, the bio-formulated sodium hyaluronate polymer matrix formulation may allow an effective therapeutic level of an active ingredient to be administered once over at least a 24 hour to several day interval. It is believed that the bio-formulated sodium hyaluronate polymer matrix formulation forms a matrix which microencapsulates, suspends and/or entraps the active ingredient such that when it is administered it is slowly released into the systemic circulatory system or muscular tissue providing a sustained and prolonged active ingredient release rate.
[0068] A wide variety of active ingredients may be used in the sustained delivery system according to this invention. These may include drugs from all major categories, and without limitation, for example, anesthetics including those used in caudal, epidural, inhalation, injectable, retrobulbar, and spinal applications, such as bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Pat. No.
3,652,762), phenacetin and salicylamide; anti-inflammatories selected from the group consisting of naproxen and indomethacin; antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxy lamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fiimarate and triprolidine;
antitussive selected from the group consisting of dextromethorphan hydrobromide and guaifenesin; expectorants such as guaifenesin;
decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine; antibiotics including amebicides, broad and medium spectrum, fungal medications, =
monobactams and viral agents and specifically including such as erythromycin, penicillin and cephalosporins and their derivatives;
bronchodilators such as theophylline, albuterol and terbutaline;
cardiovascular preparations such as diltiazem, propranolol, nifedepine and clonidine including alpha adrenoceptro agonist, alpha receptor blocking agent, alpha and beta receptor blocking agent, angiotensin converting enzyme inhibitors, beta blocking agents, calcium channel blocker, and cardiac glycosides; central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa;
metal salts such as potassium chloride and lithium carbonate; minerals selected from the group consisting of iron, chromium, molybdenum and potassium; immunomodulators; immunosuppressives; thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium; steroids and hormones including ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, human growth hormone, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatin-like compounds, urofollitropin, vasopressin, and others; and vitamins selected from water-soluble vitamins such as B complex, vitamin C, vitamin B12 and folic acid and veterinary formulations. Dosage forms may also involve the use of bupivacaine, lidocaine, vitamin B12, methyl prednisolone and adenosine-5-monophosphate sodium.
[0069] The active ingredient may be added directly to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC
or else it may be separately dissolved or disbursed in water before addition to the homogenous solution or gel of sodium hyaluronate and a non-ionic polymer such as HEC. Conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives may be added to this system.
Once all the components are blended together, for medium speed for 1 to 4 hours, the system is filled into tubes or bottles, sterilized, and stored for future use.
100701 The dosage form of this invention, in solution or suspension form, may be used topically or by injection intramuscularly, epidurally or subcutaneously. Dosages may vary from patient to patient depending on the type and severity of the condition being treated and drug being administered.
The active ingredient must be solubilized in the polymer matrix solution in order to be topically administered.
100711 The formulations of this invention formulated with an active ingredient for sustained delivery of an active ingredient may potentially be used to treat a variety of animal conditions and physical states. These systems may potentially have particular application to pain management, namely the treatment and alleviation of pain associated with any disease condition or physical state.
[0072] Without being limited to the specific pain being treated, the preparations of this invention when formulated with an active ingredient for sustained delivery of an active ingredient may potentially treat the following non-limiting locations or sources of pain: abdominal, such as in appendicitis, dysmenorrhea, musculoskeletal, pelvic, peptic ulcer, psychogenic, and urologic; acute; arm; backache; cancer; cardiac (myocardial ischemia); chest;
dental; ear; esophageal; eye; face; head; and neck; in fibromyalgia; foot; and leg; heel; ischemic pain such as in myocardial, peripheral arterial, low back, in mitral valve prolapse, in myocardial infarction, myofascial pain syndrome (fibromyalgia, fibromyositis), neck, neuropathic, neurotransmitter abnormality, nociceptive, and nocturnal pain; pelvic; pericardial; in peripheral arterial disease; phantom limb; pleuritic; polyneuropathy; postmastectomy syndrome; postoperative; psychogenic; in pulmonary embolism; in renal disease, such as colic; root avulsions; shoulder; stump; thalamic; in toes;
and toothache.
[0073] Besides chronic and intractable pain where injections of the formulation of the present invention for sustained delivery of an active ingredient may be required, the present sustained delivery formulations may potentially be used to aid in post-surgical pain treatments. With regard to uses after surgery, the formulations may be used following abdominal, cervical, thoracic or cardiac surgery, whereby multiple layers of tissue, as being sewed back together, are treated with the system. Such treatments may aid in a patient's recovery by not on:y avoiding addictive drug use such as a morphine drip, but result in the immediate and long term relief of pain to enable rapid rehabilitation.
[0074] The formulations of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art.
[0075] An effective but nontoxic amount of the system is employed in treatment. The dose regimen for administering drugs or treating various conditions may be selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the route of administration and the particular formulation or combination of active ingredients employed. Determination of the proper dose for a particular situation is within the skill of the art. Generally, amounts of the active ingredient may vary from 0.0001% to about 50% by weight of the system.
[0076] The bio-fermented sodium hyaluronate polymer matrix formulation of the present invention was found to be stable and safer than that used in the known Ionic Polymer Matrix (IPM) Wound Gel based on various testing such as Bacterial Endotoxin Test (BET), biocompatibility tests (Example 1, Example 2, and Example 3) and microbial bio-burden test (Example 7), and is of better quality based on validated chemical test (Example 5 and 6) and stability data of the product at regular interval of time (Example 4).
[0077] A new BET has been carried out in addition to the existing test methods used with the Ionic Polymer Matrix (IPM) Wound Gel product in order to ensure that the bio-fermented sodium hyaluronate polymer matrix formulation of the present invention meets the acceptable BET test limits and hence potentially reduces the incidence of pyrogenicity in the patients. Previously, there were no BET test limits set for the Ionic Polymer Matrix (IPM) Wound Gel product. Only positive or negative bacterial endotoxin test results were identified. The BET test results carried out with the bio-fermented sodium hyaluronate polymer matrix formulation product and bio-fermented sodium hyaluronate raw material indicated that the products pass the BET test. Both the raw material bio-fermented sodium hyaluronate and the finished bio-fermented sodium hyaluronate polymer matrix formulation product were tested for BET with stringent limits. The BET test were validated.
[0078] In addition, no microbiological tests for specific microorganisms or the absence of specific microorganisms were previously performed on the Ionic Polymer Matrix (IPM) Wound Gel product. Microbiological testing performed on each batch or lot of the bio-fermented sodium hyaluronate polymer matrix formulation product included all the tests as per USP<61>
(Total Aerobic Microbial Count (TAMC) and Total Combined Yeast and Mould Count (TYMC)) and USP<62> (Absence of Staphylococcus aureus, Pseudomonas aeruginosa, E. coli and Salmonella). The product passed these tests. The stability of the bio-fermented sodium hyaluronate polymer matrix formulation has now also been investigated and the product has demonstrated acceptable stability.
[0079] Previous the test methods used for the determination of sodium hyaluronate and methylparaben in the Ionic Polymer Matrix (IPM) Wound Gel product were found to be not precise, accurate or linear since the test methods were not validated. Validated analytical test methods were also developed and applied to the determination of hyaluronic acid content (see Example 13 and Example 5) and also for the determination of methylparaben content (see Example 14 and Example 6) in the bio-fermented sodium hyaluronate polymer matrix formulation.
[0080] Application of the bio-fermented sodium hyaluronate polymer matrix formulation was shown in a clinical study showing improvement in closure of incision lines in patients with toe amputations due to diabetes complications (Example 8).
[0081] In summary, the disclosed process allows for preparing sodium hyaluronate polymer matrix concentration having a high concentration of sodium hyaluronate, i.e., from about 1.5% to about 3.5% w/w. There is a significant improvement in the quality and safety of bio-fermented sodium hyaluronate polymer matrix formulation from the known Ionic Polymer Matrix (IPM) Wound Gel due to the change in the source of sodium hyaluronate from avian (rooster comb) to a bio-fermented source obtained from a bacterial fermentation process. Additional improvements are due to the development and application of additional quality testing such as BET and bioburden test (USP 62) and improved Biocompatability test (Cytoxicity test) results, the development and application of test methods for sodium hyaluronate and the preservative methylparaben, and the use of compendial or pharmaceutical grade raw materials.
[0082] Table 2 below summarizes the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel.
Table 2. Summary of the testing regimen of the formulation of the present invention in comparison to the testing regimen of IPM Would Gel.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Bacterial Endotoxin Test BET: Negative BET test limits established.
The test method was based old Rabbit The test method is based on LAL test Pyrogenicity test. (Limulus amebocyte lysate test) method which is better quantified.
BET method validated Test for Specified Microorganisms Test for Specified Microorganisms including:
Pseudomonas aeruginosa: Negative Staphylococcus aureus: Negative E. coli: Negative Salmonella: Negative Conducted per USP<62>/Ph. Eur.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention Validated Test Methods Analytical test method validated for the determination of sodium hyaluronate content in the sodium hyaluronate bio-fermented formulation.
Analytical test method validated for the determination of methylparaben content in the sodium hyaluronate biofermented formulation.
Viscosity Viscosity (II) = 10, 000 ¨ 50,000 cps (recorded).
Anti-microbial Effectiveness Test (AET) AET: Meets USP requirements (stability test) (USP <51>) Methylparaben test Methylparaben test (Limit 90¨ 110%) (stability test) Biocompatibility Test Test for Skin Irritation, Guinea pig Test for Skin Irritation, Guinea pig Maximization Sensitization Test and Maximization Sensitization Test and Cytotoxicity Test were performed. Cytotoxicity Test were performed.
Sodium hyaluronate bio-fermented IPM Wound Gel formulation of the present invention However, Cytotoxicity test showed that the test article had a smaller zone of lysis (i.e. less cytotoxic) as compared to the IPM Wound Gel.
Stability 1 year long-term stability data available. 18 months long-term stability data available.
100831 In the examples below, results of testing of bio-fermented sodium hyaluronate polymer matrix formulation comprising sodium hyaluronate (2.5%, w/w), hydroxyethyl cellulose (I% w/w), methylparaben (0.2% w/w), polyethylene glycol (3%, w/w) and purified water, USP (approx. 93%, w/w) made from raw materials of preferred grades and by preferred process of the present invention (referred to as the "test article", also referred to "IPM
Wound Gel Bio") are presented.
Example 1: Test for Skin Irritation [0084] The test article, bio-fermented sodium hyaluronate polymer matrix formulation was evaluated for primary skin irritation in accordance with the guidelines of ISO 10993-10, Biological evaluation of medical devices ¨ Part 10: Tests for irritation and skin sensitization.
[0085] Two 0.5 mL portions of the test article and control article (namely, saline solution, i.e., 0.9% Sodium chloride solution) were topically applied to the skin of each of three rabbits and left in place for 24 hours. The sites were graded for erythema and edema at 1, 24, 48 and 72 hours after removal of the single sample application.
[0086] There was no erythema and no edema observed on the skin of the animals treated with the test article. The Primary Irritation Index for the test article was calculated to be 0Ø The response of the test article was categorized as negligible.
Example 2: Guinea pig Maximization Sensitization Test [0087] The test article was evaluated for the potential to cause delayed dermal contact sensitization in a guinea pig maximization test. This study was conducted based on the requirements of ISO 10993-10, Biological evaluation of medical devices ¨ Part 10: Tests for irritation and skin sensitization.
Dose determination was performed to determine a suitable test article concentration for testing. The test article solution was intradermally injected and occlusively patched to ten test guinea pigs. The control article was similarly injected and occlusively patched to five control guinea pigs. Following a recovery period, the test and control animals received challenge patches of the test solution and the vehicle control article. All sites were scored for dermal reactions at 24 and 48 hours after patch removal.
[0088] The test article solution showed no evidence of causing delayed dermal contact sensitization in the guinea pig. The test article was not considered a sensitizer in the guinea pig maximization test.
Example 3: Cytotoxicity Test [0089] The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e. less cytotoxic) as compared to the previous known Ionic Polymer Matrix (IPM) Wound Gel. The details of the test performed is provided below:
[00901 The test article was evaluated to determine the potential for cytotoxicity based on the requirements 9f ISO 10993-5: Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity. Triplicate wells were dosed with 0.1 mL of the test article placed on a filter (test filter disc).
Triplicate wells were dosed with 0.1 mL of 0.9% sodium chloride solution placed on a filter disc (filter disc control). Triplicate wells were dosed with a 1 cm length portion of high density polyethylene as a negative control.
[0091] Triplicate wells were dosed with a 1 cm x 1 cm portion of latex as a positive control. Each was placed on an agarose surface directly overlaying a sub confluent monolayer of L-929 mouse fibroblast cells. After incubating at 37 C in the presence of 5% CO2 for 24 hours, the cultures were examined macroscopically and microscopically for any abnormal cell morphology and cell lysis.
[0092] The in-vitro cytotoxicity test showed that the test article had a smaller zone of lysis (i.e., less cytotoxic) as compared to the previously known Ionic Polymer Matrix (IPM) Wound Gel, as shown in Table below.
Zone of lysis (mm) Test article IPM Wound Gel Test Disc I 1 4 Test Disc 2 1 4 Test Disc 2 1 4 Example 4: Stability of Bio-fermented Sodium Hyaluronate Polymer Matrix Formulation 100931 Stability of the test article was studied after incubation at various temperatures and time-intervals.
100941 Methods: The concentrations of sodium hyaluronate were measured after incubation periods of various lengths. Other test parameters included appearance test, methylparaben assay, pH and viscosity.
[0095] Results: Examples of test results are shown in Table # 1. All concentrations of sodium hyaluronate are in % w/w.
Temperature Sodium hyaluronate % (w/w) Month 0 Month 3 Month 6*
25 C and 60%RH 2.48 2.51 2.52 30 C and 65%RH 2.48 Not Scheduled 2.53 30 C and 75%RH 2.48 2.47** 2.55 40 C and 75%RH 2.48 2.52 2.46 *It has been seen that the response factor of the calibration curve increase during the stability study. This is probably due to absorption of water for the standard.
The response factor has increased to 104% from the zero value to the six months value (103% from zero to three months). The results are therefore false higher.
**% RSD for 2 in weights (4 injections) 4.25%.
All other test parameters were all well within the stability test limits.
[0096] Conclusions: It can be concluded from the results presented above that the test article is stable over a prolonged period as substantiated by the results from the accelerated stability tests at 40 C and 75%RH.
Example 5: Method validation of determination of sodium hyaluronate content in the test article [0097] An HPLC method was validated for the determination sodium hyaluronate in the test article was developed. An HPLC System with a UV
detector was used.
[0098] Results and Discussion: The average assay obtained for sodium hyaluronate in the test article was 2.545 % w/w and the % relative standard deviation was 0.32. Over a range of 1.14% (or 114 g/mL) to 3.99% (or 399 ps/mL) the assay showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.481 for the % Label claim of sodium hyaluronate. Hence the HPLC method used for the determination of sodium hyaluronate content (or assay) has been validated and verified.
Example 6: Method validation for the determination of methylparaben content in the test article [0099] An HPLC method was validated for the determination methylparaben content in the test article was developed. An HPLC System with a UV detector was used.
[00100] Results and Discussion: The average assay obtained for methylparaben was 103.3% and the % relative standard deviation was 0.56. Over a range of 0.06% to 0.18% the assay of methylparaben showed good linearity with a correlation coefficient greater than 0.999. A precision study showed that the % relative standard deviation was approximately 0.096 for the Label claim of methylparaben. Hence the HPLC method used for the determination of methylparaben content (or assay) has been validated and verified.
Example 7: Antimicrobial Effectiveness Testing (AET) [001011 Antimicrobial efficacy testing (AET) measures the effectiveness of antimicrobial preservatives that are. added to inhibit the growth of microorganisms that may be introduced inadvertently during the manufacturing process or during product use. Antimicrobial effectiveness testing should be performed, on all aqueous-based products that are injectable, ophthalmic, otic, nasal, oral, and topical.
[00102] The antimicrobial preservative in the test article is methylparaben at target concentration of 0.2% w/w.
1001031 Methods: The AET was performed on the test article as per USP<51>
compendial standard using the all five microorganisms ¨ Escherichia coli (fermentative gram negative bacteria), Pseudomonas aeruginosa (non-fermentative gram negative bacteria), Staphylococcus aureus(gram positive bacteria), Aspergillus niger (mold or fungus) and Candida albicans (yeast).
The Antimicrobial Effectiveness Testing was performed on three lots at 18 months' time-point Long-Term Stability Study.
[00104] Results: The test results indicated that the proposed preservative system and concentration met the preservative effectiveness test requirements for Category 2 products (as per USP, topically used products made with aqueous bases or vehicles, non-sterile nasal products, and emulsions, including those applied to mucous membranes).
[00105] Conclusion: The preservative system has been demonstrated to be suitable and effective in protecting the test article from microbial growth or from inadvertently introduced microorganisms.
Example 8: Closure of incision lines in patients with digit amputations [00106] Study design: IMP Wound Gel Bio was used in the healing of incision lines after digit amputations. Over a period of 9 months, 116 amputations were performed on diabetic patients with non-healing, digital diabetic ulceration. Blood supply was never perfect in those patients, however, is also not profoundly impaired. The treatment protocol was to apply a thin film of IPM Wound Gel Bio along the incision line, on a daily basis, with the wound site covered with foam dressing. The patients were seen 1 week postoperatively and again 2 weeks later.
[00107] Results: The results that 94 (81%) of those patients healed, with complete epithelialization of the incision line within 1-2 weeks. This is in contrast to a typical 4 week healing time that was observed prior to using IPM
Wound Gel Bio. In addition, the complication rate was correspondingly low as there was no incision line dehiscence or infection.
1001081 Conclusions: The overall experience with IPM Wound Gel Bio has been extremely positive. Particularly striking was the consistency in the healing times of the incision lines, given that the patients were very sick patients with profound underlying end organ damage. The healing mechanism in these individuals is grossly impaired and amputation with primary closure is frequently fraught with postoperative complications. The rate of these complications was reduced with the introduction of IPM Wound Gel Bio as a postoperative treatment protocol and as such the need for ongoing homecare was reduced as well the patient's return to work or normal activities of daily living was accelerated.
Example 9: A formulation containing sodium hyaluronate for application to wounds Table 3. A preferred biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate Ingredient Amounts (% w/w) Sodium hyaluronate 2.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit [00109] The above batch contained a sodium hyaluronate as a humectant and matrix forming agent, hydroxyethylcellulose is a thickening agent and helps in forming polymer matrix, polyethylene glycol is a solvent, methylparaben as preservative and water as a solvent. Several experiments were done and the optimum pH range was established to be 5.0 to 7Ø The optimum viscosity range of the solution was established to be in the range of 10,000 ¨ 50,000 cps. The product is found to be stable.
100110] The formulation in Table 1 was prepared by adding methylparaben to water in a suitable container and mixing at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate (having a molecular weight from 600,000 ¨ 800,000 Daltons) in a steady flow to the mixture gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container (for about 1 hour). Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
1001111 In a separate container dissolve 1% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours).
[00112] The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed followed by low speed for long period (about 4 hours) until a homogenous solution is produced.
[00113] Add polyethylene glycol into the mixture while mixing at a medium speed. Continue mixing at medium speed for about 1 hour. Reduce the speed and continue mixing at low speed for a few hours (minimum of about 3 hours).
The bulk gel is then filled in tubes or bottles and capped.
Example 10: A formulation containing sodium hyaluronate and pantothenic acid for topical use [00114] A formulation containing sodium hyaluronate and pantothenic acid may be used in the treatment of damaged skin and can be used in the treatment of atopic dermatitis.
Table 4. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and pantothenic acid.
Ingredient Amounts (/0 w/w) Sodium hyaluronate 1.5 Hydroxyethylcellulose 1.0 Polyethylene glycol 3.0 Ingredient Amounts CAD w/w) Pantothenic acid (Vitamin B5) 1.5 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit 1001151 The formulation in Table 2 was prepared as detailed below:
First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the dissolvent thickens and the spin stays while charging sodium hyaluronate in a suitable container. Mix for few hours (about 2 hours) at medium speed.
Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyalorunate polymer has dissolved into the mixture and a crystal-clear viscous solution has formed.
[00116] In a separate container dissolve 1.0% hydroxyethylcellulose in purified water while stirring at medium speed and mix well. Continue stirring for a few hours (from about 1 to about 2 hours).
[00117] Next the hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed until a homogenous solution is produced. The resulting solution is mixed at medium speed for long period (overnight, or about 8 hours to about 15 hours) until a homogenous solution is produced. Add polyethylene glycol into the mixture while mixing at a medium speed for about 1 hour. This is followed by the addition of pantothenic acid and mixing well at medium speed for few hours (about 2 hours) until dissolved and the gel is homogeneous. The bulk gel is then filled in tubes or bottles and capped.
Example 11: A formulation containing sodium hyaluronate and diclofenac sodium for topical use [00118] A formulation containing sodium hyaluronate and diclofenac sodium can be used to treat actinic keratosis and in the relief of musculoskeletal pain in areas affected by the pain. Such areas include, but are not limited to, knees, ankles, feet, back, neck, elbows and hips.
Table 5. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate and dicloflenac sodium. The formulation was found to be stable.
Ingredient Amounts (% w/w) Dicloflenac sodium 3 Sodium hyaluronate 2.3 Hydroxyethylcellulose 0.7 Methoxypolyethylene glycol 10 Methylparaben 0.3 Water q.s.*
Total 100 = quantum sufficit [00119] The formulation in Table 3 was prepared as follows:
First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then slowly add sodium hyaluronate to it while gradually increasing the stirring speed from medium to high as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (about 8 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous.
[00120] In a separate container dissolve 0.7% hydroxyethylcellulose in purified water while stirring at low to medium speed and mix well. Continue stirring for few hours (from about 1 to about 2 hours).
[00121] The resulting hydroxyethylcellulose solution is added to the sodium hyaluronate solution and mixed at medium speed for a long period (from about to about 15 hours) until a homogenous solution is produced.
[00122] Add methoxypolyethylene glycol (MPEG) 10% into the mixture. The mixing speed should be increased for the mixture while this step is being performed to a high speed. The resulting mixture thus formed should be allowed to mix at medium speed for a few hours (from about 3 to about 4 hours).
1001231 Using safe techniques, 3% diclofenac sodium should be slowly added to the mixture. Again the mixing speed for the purpose of addition of diclofenac should be increased to high speed, and the addition of entire quantity of diclofenac should be completed within a short duration (about 15 minutes).
1001241 The final- mixture is clear with a slight green tint following further mixing for long duration (about 15 to about 20 hours) at medium speed. The final product should be transferred, using aseptic technique, to a bulk storage container and then the bulk gel is filled in tubes or bottles and capped.
Example 12: A formulation containing sodium hyaluronate for treating vaginal dryness containing using niacin and glycerin Table 6. A biofermented sodium hyaluronate formulation containing a high concentration sodium hyaluronate And niacin and glycerin.
Ingredient Amounts (% w/w) Niacin 0.85 Ingredient Amounts (% w/w) Glycerin 3 Sodium hyaluronate 1.5 Hydroxyethylcellulose 0.7 Polyethylene glycol 3 Methylparaben 0.2 Water q.s.*
Total 100 = quantum sufficit ** Glycerin USP should be used Not More Than 0.10% each for diethylene glycol and ethylene glycol is found in Glycerin as per USP]
[00125] A transdermal preparation of niacin (0.85%) and glycerin (3%) formula for Table 4 is prepared in the following manner. First, add methylparaben to water in a suitable container and mix at medium speed for few hours (about 2 hours). Ensure that methylparaben is completely dissolved. Then add sodium hyaluronate slowly in a steady flow in water while gradually increasing the stirring speed from medium to high speed as the mixture thickens and the spin stays while charging sodium hyaluronate in a suitable container for about 1 hour. Mix for few hours (about 2 hours) at medium speed. Continue the mixing at low speed for long duration (overnight, or about 8 hours to about 15 hours) until all of the sodium hyaluronate polymer has dissolved into water and a crystal-clear viscous solution has formed. The gel should be homogenous.
[00126] Next, a solution is prepared by adding 0.7% HEC to purified water while stirring at low to medium speed and mixing well. Continue stirring for few hours (from about 1 to about 2 hours). The resulting solution is then added to the above formed mixture of sodium hyaluronate and mixed at medium speed for a long period (overnight, or about 8 hours to about 15 hours) to form a sodium hyaluronate/HEC polymer matrix.
[00127] To the resulting mixture PEG is added and stirred at medium speed for a few hours (about 2.5 hours).
[00128] Then, niacin and glycerin is added to the HA/HEC polymer matrix. The mixture is stirred at low speed for few hours (about 2 hours). The bulk gel is either stored for filling or a 0.5 to 0.75 ml of the resulting gel is loaded into syringes and stored in a refrigerator.
Example 13: Test method for determination of sodium hyaluronate [00129] An HPLC test method for the determination of sodium hyaluronate in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed.
Column BioSep SEC-s2000, 300 mm x 7.8 mm, 5pt Detection UV @205 nm Column Temp.: 40 C
Injection Volume: 10 piL
Flow Rate: 1.3 mUmin Run Time: 20 min Mobile Phase: 50 mM KH2PO4, pH adjusted to 7.0 [00130] The assay is based on HPLC analysis with a size exclusion analytical column and UV detection at 205 nm.
Example 14: Test method for determination of methylparaben [00131] An HPLC test method for the determination of methylparaben in the test article (sodium hyaluronate bio-fermented wound gel formulation) was developed.
Column Kinetex, C8, 100 mm x 4.6 mm, 2:6 t, 100 A
Detection UV g254 nm Column Temp.: 35 C
Injection Volume: 20 !IL
Flow Rate: 1.4 mL per min Run Time: 2 min Mobile Phase: 60:40 (v/v) 0.1% TFA in Milli-Q Water;
0.1% TFA in Acetonitrile 1001321 The assay is based on HPLC analysis with reverse phase C8 analytical column and UV detection at 254 nm.
1001331 Although specific embodiments of the invention have been described, it will be apparent to one skilled in the art that variations and modifications to the embodiments may be made within the scope of the following claims.
Example 15: Pharmacokinetics and Bioavailability of 3% Diclofenac IPM
Matrix 2.3 % Sodium Hyaluronate Gel [00134] An open label, single centre, single dose, single dose, one-treatment, one period, pharmacokinetic and bioavailability study was carried out. Six normal, healthy, non-smoking males between the ages of 18-45 were administered 3% diclofenac IPM matrix gel made with 2.3% avian sodium hyalorunate, which was applied once for a 24 hour period. A total of 4 cc was the applied to the anterior right knee of each subject. Pharmacokinetics and bioavailability of the single dose application was assessed. A total 18 blood samples and 8 urine samples were collected for each subject during the 24 hour period after administration. The concentration of diclofenac was assessed for each sample. Diclofenac plasma and urine concentrations are presented in Table 7 and 8. Diclofenac was found in samples from all subjects. Concentrations varied from subject to subject, but this was normal for diclofenac.
Table 7. Diclofenac Plasma Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Subject Hour Min Diclofenac Concentration Found Ing/m11 Subject Hour Min Diclofenac Concentration Found [ng/m11 1 1 0 0.074 1 1 5 0.228 1 2 0 0.385 1 2 5 0.487 1 3 0 0.655 1 3 5 0.859 1 4 0 0.807 1 5 0 0.944 1 6 0 1.40 1 7 0 1.53 1 8 0 1.75 1 12 0 1.57 1 16 0 1.93 1 24 0 2.33 2 1 0 0.042 2 1 5 0.191 2 2 0 0.369 2 2 5 0.403 2 3 0 0.471 2 3 5 0.410 2 4 0 0.496 2 5 0 0.814 2 6 0 1.03 2 7 ________ 0 1.01 2 8 0 1.33 2 12 0 1.25 2 16 0 1.98 2 24 0 2.44 3 2 0 0.049 3 2 5 0.184 3 3 0 0.118 3 3 5 0.184 3 4 0 0.232 3 5 0 0.244 3 6 0 0.377 3 7 0 0.489 , Subject Hour Min Diclofenac Concentration Found ing/mij 3 8 0 0.532 3 12 0 0.944 3 16 0 1.64 3 24 0 2.92 4 2 5 0.090 4 3 5 0.053 4 4 0 0.045 4 5 0 0.084 4 6 0 0.107 4 7 0 0.312 4 8 0 0.383 4 12 0 0.563 4 16 0 0.940 4 24 0 0.429
5 0 25 BLQ
5 2 5 _______________________ 0.046 5 3 0 0.066 5 3 5 0.081 5 4 0 0.150 5 5 0 0.367 5 6 0 0.448 5 7 0 0.742 5 8 0 1.07 5 12 0 3.04 5 16 0 3.65 5 24 0 2.17
5 2 5 _______________________ 0.046 5 3 0 0.066 5 3 5 0.081 5 4 0 0.150 5 5 0 0.367 5 6 0 0.448 5 7 0 0.742 5 8 0 1.07 5 12 0 3.04 5 16 0 3.65 5 24 0 2.17
6 0 0 BLQ
_ 6 1 5 0.023 6 2 0 0.072 Subject Hour Min Diclofenac Concentration Found [lig/mil 6 2 5 0.109 6 3 0 0.215 6 3 _______ 5 0.287 6 4 0 0.385 6 5 0 0.772 6 6 0 1.23 6 7 0 1.60 6 8 0 1.98 6 12 0 1.34 6 16 0 1.63 6 24 0 1.31 * BLQ = below the lower limit of quantification (0.02 ng/ml) Table 8. Diclofenac Urine Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Subject Hour Diclofenac Concentration Found Ing/mill 1 pre 0.0 hr BLQ
1 0.0 - 2.0 hr 0.012 1 2.0 - 4.0 hr 0.117 1 4.0 -6.0 hr 0.704 1 6.0 - 8.0 hr 3.58 1 8.0 - 10.0 hr 3.98 1 10.0- 12.0 hr 3.83 1 12.0 - 24.0 hr 2.81 2 pre 0.0 hr BLQ
2 0.0 -2.0 hr 0.042 2 2.0 -4.0 hi 0.434 2 4.0 -6.0 hr 0.428 2 6.0 - 8.0 hr 0.724 2 8.0- 10.0 hr 2.59 2 10.0- 12.0 hr 0.785 2 12.0 -24.0 hr 2.67 3 pre 0.0 hr BLQ
3 0.0 - 2.0 hr BLQ
3 2.0 -4.0 hr BLQ
3 4.0 - 6.0 hr 0.144 3 6.0 - 8.0 hr 0.315 3 8.0 - 10.0 hr 0.748 3 10.0- 12.0 hr 0.427 3 12.0 - 24.0 hr 6.04 4 pre 0.0 hr BLQ
Subject Hour Diclofenac Concentration Found [ng/m11 4 0.0 -2.0 hr BLQ
4 2.0 -4.0 hr 0.051 4 4.0 - 6.0 hr 0.120 4 6.0 - 8.0 hr 0.356 4 8.0 - 10.0 hr 0.654 4 10.0- 12.0 hr 4.95 4 12.0 - 24.0 hr 2.24 pre 0.0 hr BLQ
5 0.0 -2.0 hr 0.595 5 2.0 -4.0 hr 0.097 5 4.0 - 6.0 hr 0.804 5 6.0 -8.0 hr 2.29 5 8.0 - 10.0 hr 0.763 5 10.0 - 12.0 hr 3.28 5 12.0 - 24.0 hr 7.76 6 pre 0.0 hr BLQ
6 0.0 - 2.0 hr BLQ
6 2.0 -4.0 hr 0.384 6 4.0 - 6.0 hr 3.52 6 6.0 - 8.0 hr 13.9 6 8.0 - 10.0 hr 11.0 6 10.0 - 12.0 hr 2.71 6 12.0 - 24.0 hr 2.27 * BLQ = below the lower limit of quantification (0.01 ng/ml) Example 16: Efficacy of 3% diclofenac IPM 2.3% sodium hyalorunate matrix gel by topical application in treating painful musculoskeletal conditions, principally involving the relief of pain and muscle spasm.
[00135] 23 patients with musculoskeletal pain, at a pain clinic, were asked to volunteer to test 3% diclofenac IPM 2.3% sodium hyalorunate matrix gel gel made with avian sodium hyalorunate. The gel was applied liberally on the skin four times a day over fle area with the musculoskeletal problem causing the pain. The patients were asked to assess 34 criteria to estimate their musculoskeletal pain or stiffness on a visual analogue scale, graded 0 - 10 at the first visit. 17 patients were assessed on only one criterion but five patients were assessed on two criteria as follows: right and left ankle, neck pain and stiffness, headache and neck pain and shoulder and neck pain to make a total of 34 criteria. They were then given a supply of diclofenac gel to apply to painful area and asked to grade the change in the pain on a nine point scale from very much worse through no change to very much better. The patients were then given a further one week supply of gel and they did a second self assessment at the end of the second week's treatment.
[00136] After one week's treatment, of 23 patients' 27 criteria, eight criteria reported no change, 19 reported an improvement varying between somewhat better and no pain and no one had worse pain. The improved group consisted of ten, one, six and two patients being respectively somewhat better, better, much better and having no pain. No patient had worse pain.
[00137] After two week's treatment, which essentially are similar to the results at one week, but one patient's criterion reported being somewhat worse, six showed no change and twenty patients' criteria reported improvement with feeling better.
[00138] Combining the results at one and two weeks produced a similar result to each of them. Using a visual analogue scale with only one criterion for each patient, the average figure falls after diclofenac and rises when it is discontinued [00139] In conclusion, diclofenac gel is an effective preparation for the transcutaneous relief of arthritis and musculoskeletal pain. It has good patient acceptance, is easily administered, causes no serious side-effects, and avoids the gastrointestinal upset that so often accompanies oral NSAID use.
[00140] There is no biological reason to anticipate different clinical behavior of ionic polymer matrix gel manufactured with sodium hyaluronate from a bacterial source of the present invention compared with that manufactured with hyaluronate from an avian source used in example 15 and 16. Clinical data developed for IPM Wound Gel applies to IPM Wound Gel Bio of the present invention.
_ 6 1 5 0.023 6 2 0 0.072 Subject Hour Min Diclofenac Concentration Found [lig/mil 6 2 5 0.109 6 3 0 0.215 6 3 _______ 5 0.287 6 4 0 0.385 6 5 0 0.772 6 6 0 1.23 6 7 0 1.60 6 8 0 1.98 6 12 0 1.34 6 16 0 1.63 6 24 0 1.31 * BLQ = below the lower limit of quantification (0.02 ng/ml) Table 8. Diclofenac Urine Concentration (ng/mL) Measured in Samples from Subjects Using 3% Diclofenac Gel Subject Hour Diclofenac Concentration Found Ing/mill 1 pre 0.0 hr BLQ
1 0.0 - 2.0 hr 0.012 1 2.0 - 4.0 hr 0.117 1 4.0 -6.0 hr 0.704 1 6.0 - 8.0 hr 3.58 1 8.0 - 10.0 hr 3.98 1 10.0- 12.0 hr 3.83 1 12.0 - 24.0 hr 2.81 2 pre 0.0 hr BLQ
2 0.0 -2.0 hr 0.042 2 2.0 -4.0 hi 0.434 2 4.0 -6.0 hr 0.428 2 6.0 - 8.0 hr 0.724 2 8.0- 10.0 hr 2.59 2 10.0- 12.0 hr 0.785 2 12.0 -24.0 hr 2.67 3 pre 0.0 hr BLQ
3 0.0 - 2.0 hr BLQ
3 2.0 -4.0 hr BLQ
3 4.0 - 6.0 hr 0.144 3 6.0 - 8.0 hr 0.315 3 8.0 - 10.0 hr 0.748 3 10.0- 12.0 hr 0.427 3 12.0 - 24.0 hr 6.04 4 pre 0.0 hr BLQ
Subject Hour Diclofenac Concentration Found [ng/m11 4 0.0 -2.0 hr BLQ
4 2.0 -4.0 hr 0.051 4 4.0 - 6.0 hr 0.120 4 6.0 - 8.0 hr 0.356 4 8.0 - 10.0 hr 0.654 4 10.0- 12.0 hr 4.95 4 12.0 - 24.0 hr 2.24 pre 0.0 hr BLQ
5 0.0 -2.0 hr 0.595 5 2.0 -4.0 hr 0.097 5 4.0 - 6.0 hr 0.804 5 6.0 -8.0 hr 2.29 5 8.0 - 10.0 hr 0.763 5 10.0 - 12.0 hr 3.28 5 12.0 - 24.0 hr 7.76 6 pre 0.0 hr BLQ
6 0.0 - 2.0 hr BLQ
6 2.0 -4.0 hr 0.384 6 4.0 - 6.0 hr 3.52 6 6.0 - 8.0 hr 13.9 6 8.0 - 10.0 hr 11.0 6 10.0 - 12.0 hr 2.71 6 12.0 - 24.0 hr 2.27 * BLQ = below the lower limit of quantification (0.01 ng/ml) Example 16: Efficacy of 3% diclofenac IPM 2.3% sodium hyalorunate matrix gel by topical application in treating painful musculoskeletal conditions, principally involving the relief of pain and muscle spasm.
[00135] 23 patients with musculoskeletal pain, at a pain clinic, were asked to volunteer to test 3% diclofenac IPM 2.3% sodium hyalorunate matrix gel gel made with avian sodium hyalorunate. The gel was applied liberally on the skin four times a day over fle area with the musculoskeletal problem causing the pain. The patients were asked to assess 34 criteria to estimate their musculoskeletal pain or stiffness on a visual analogue scale, graded 0 - 10 at the first visit. 17 patients were assessed on only one criterion but five patients were assessed on two criteria as follows: right and left ankle, neck pain and stiffness, headache and neck pain and shoulder and neck pain to make a total of 34 criteria. They were then given a supply of diclofenac gel to apply to painful area and asked to grade the change in the pain on a nine point scale from very much worse through no change to very much better. The patients were then given a further one week supply of gel and they did a second self assessment at the end of the second week's treatment.
[00136] After one week's treatment, of 23 patients' 27 criteria, eight criteria reported no change, 19 reported an improvement varying between somewhat better and no pain and no one had worse pain. The improved group consisted of ten, one, six and two patients being respectively somewhat better, better, much better and having no pain. No patient had worse pain.
[00137] After two week's treatment, which essentially are similar to the results at one week, but one patient's criterion reported being somewhat worse, six showed no change and twenty patients' criteria reported improvement with feeling better.
[00138] Combining the results at one and two weeks produced a similar result to each of them. Using a visual analogue scale with only one criterion for each patient, the average figure falls after diclofenac and rises when it is discontinued [00139] In conclusion, diclofenac gel is an effective preparation for the transcutaneous relief of arthritis and musculoskeletal pain. It has good patient acceptance, is easily administered, causes no serious side-effects, and avoids the gastrointestinal upset that so often accompanies oral NSAID use.
[00140] There is no biological reason to anticipate different clinical behavior of ionic polymer matrix gel manufactured with sodium hyaluronate from a bacterial source of the present invention compared with that manufactured with hyaluronate from an avian source used in example 15 and 16. Clinical data developed for IPM Wound Gel applies to IPM Wound Gel Bio of the present invention.
Claims (12)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable topical polymer matrix composition comprising:
1.5% w/w to about 3.5% w/w bio-fermented sodium hyaluronate;
0.1 % w/w to about 2.0% w/w hydroxyethylcellulose;
2% w/w to about 4% w/w of the polyethylene glycol (PEG);
0.1% w/w to 0.3% w/w methylparaben; and water;
wherein the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has an average molecular weight between about 600,000 Daltons to about 800,000 Daltons, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, Total Combined Yeast and Mould Count (TYMC) of less than or equal to 10 cfu/q, Bacterial Endotoxin Test (BET) score of less than or equal to 0.5 Ili/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli , and Salmonella sp.;
wherein the hydroxyethylcellulose is of pharmaceutical grade and has a Total Aerobic Microbial Count (TAMC) of less than 100 cfu/g;
wherein the polyethylene glycol (PEG) is of pharmaceutical grade, wherein the average molecular weight of the PEG is 200 and wherein the PEG has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25% w/w; TAMC
of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL;
wherein the methylparaben is of pharmaceutical grade and has a TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; and wherein the water is purified having a TAMC of less than 100 cfu/mL and a BET
score of less than 0.25 EU/mL.
1.5% w/w to about 3.5% w/w bio-fermented sodium hyaluronate;
0.1 % w/w to about 2.0% w/w hydroxyethylcellulose;
2% w/w to about 4% w/w of the polyethylene glycol (PEG);
0.1% w/w to 0.3% w/w methylparaben; and water;
wherein the bio-fermented sodium hyaluronate is of pharmaceutical grade according to the European Pharmacopoeia, has an average molecular weight between about 600,000 Daltons to about 800,000 Daltons, has nucleic acid content of less than or equal to 0.5%, has protein content of less than or equal to 0.3%, Total Combined Yeast and Mould Count (TYMC) of less than or equal to 10 cfu/q, Bacterial Endotoxin Test (BET) score of less than or equal to 0.5 Ili/mg, and tests absent for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli , and Salmonella sp.;
wherein the hydroxyethylcellulose is of pharmaceutical grade and has a Total Aerobic Microbial Count (TAMC) of less than 100 cfu/g;
wherein the polyethylene glycol (PEG) is of pharmaceutical grade, wherein the average molecular weight of the PEG is 200 and wherein the PEG has a combined ethylene glycol and diethylene glycol content of less than or equal to 0.25% w/w; TAMC
of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL;
wherein the methylparaben is of pharmaceutical grade and has a TAMC of less than 100 cfu/mL and TYMC of less than or equal to 10 cfu/mL; and wherein the water is purified having a TAMC of less than 100 cfu/mL and a BET
score of less than 0.25 EU/mL.
2. The polymer matrix composition of claim 1, further comprising at least one active ingredient.
3. The polymer matrix composition of claim 2, wherein the at least one active ingredient is selected from the group consisting of pantothenic acid, diclofenac sodium, niacin and glycerin.
4. The polymer matrix composition of claim 1, further comprising 0.1-2.0%
w/w of a non-ionic polymer, other than hydroxyethylcellulose, selected from a group consisting of polyvinylpyrrolidone, poloxamer, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymer, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymer, polyacrylamide, polyethylene oxide copolymer, neutralized polyacrylic acid, polysorbate, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) alpha, omega-dialkyl-ethoxylates, and mixtures thereof.
w/w of a non-ionic polymer, other than hydroxyethylcellulose, selected from a group consisting of polyvinylpyrrolidone, poloxamer, copovidone, polyvinyl alcohol, cellulose derivatives, sorbitol based polymer, locus bean gum, guar gum, maltodextrin, vinyl pyrrolidone copolymer, polyacrylamide, polyethylene oxide copolymer, neutralized polyacrylic acid, polysorbate, ethoxylates, polyalcohols, polyethylene glycol, methoxy methoxypolyethylene glycol (MPEG) alpha, omega-dialkyl-ethoxylates, and mixtures thereof.
5. The polymer matrix composition of claim 1, wherein the bio-fermented sodium hyaluronate is present in an amount of 2.3 to 27% w/w, and the hydroxyethylcellulose is present in an amount of 0.5 to 1.5% w/w.
6. The polymer matrix composition of claim 1, wherein the bio-fermented sodium hyaluronate is present in an amount of 2.5% w/w, the hydroxyethylcellulose is present in an amount of 1 % w/w, and the polyethylene glycol is present in an amount of 3.0% w/w.
7. The polymer matrix composition of claim 3, wherein the active ingredient is diclofenac sodium.
8. The polymer matrix composition of claim 1, wherein the methylparaben is present in an amount of 0.2 %w/w.
9. Use of the stable topical polymer matrix composition claim 3, to treat a condition selected from the group consisting of postoperative incisions, dermatological conditions, burns, damaged skin, atopic dermatitis, vaginal dryness, actinic keratosis and musculoskeletal pain.
10. The use of claim 9, wherein the active ingredient is pantothenic acid and the condition is damaged skin or atopic dermatitis.
11. The use of claim 9, wherein the active ingredient comprises niacin and glycerin and the condition is vaginal dryness.
12. The use of claim 9, wherein the active ingredient is diclofenac sodium and the condition is actinic keratosis and musculoskeletal pain.
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CA2896038A CA2896038C (en) | 2015-07-03 | 2015-07-03 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
EP15178106.9A EP3111925A1 (en) | 2015-07-03 | 2015-07-23 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
US14/818,810 US9821005B2 (en) | 2015-07-03 | 2015-08-05 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
CN202210680603.5A CN115025114A (en) | 2015-07-03 | 2016-01-07 | Polymer matrix compositions comprising high concentrations of biologically fermented sodium hyaluronate and uses thereof |
CN201610010139.3A CN106309473A (en) | 2015-07-03 | 2016-01-07 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
MX2016008559A MX360365B (en) | 2015-07-03 | 2016-06-27 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof. |
CR20180014A CR20180014A (en) | 2015-07-03 | 2016-06-30 | TOPICAL POLYMER MATRIX COMPOSITIONS THAT INCLUDE A HIGH CONCENTRATION OF BIO-FERMENTED SODIUM Hyaluronate AND ITS USES |
PCT/CA2016/050774 WO2017004706A1 (en) | 2015-07-03 | 2016-06-30 | Topical polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
KR1020217004367A KR20210020171A (en) | 2015-07-03 | 2016-06-30 | Topical polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
KR1020187002995A KR20180059748A (en) | 2015-07-03 | 2016-06-30 | Highly concentrated bioceramics composed of biodegradable sodium hyaluronate and its use |
AU2016289095A AU2016289095B2 (en) | 2015-07-03 | 2016-06-30 | Topical polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
KR1020237011305A KR20230050475A (en) | 2015-07-03 | 2016-06-30 | Topical polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
ARP160102016A AR107212A1 (en) | 2015-07-03 | 2016-07-01 | TYPICAL POLYMER MATRIX COMPOUNDS THAT INCLUDE A HIGH CONCENTRATION OF BIOFERMENTED SODIUM HIALURONATE AND ITS USES |
US15/727,820 US10322142B2 (en) | 2015-07-03 | 2017-10-09 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
ECIEPI201781071A ECSP17081071A (en) | 2015-07-03 | 2017-12-07 | TOPICAL POLYMERIC MATRIX COMPOSITIONS INCLUDING A HIGH CONCENTRATION OF BIO-FERMENTED SODIUM HYALURONATE AND ITS USES |
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CA2896038A Active CA2896038C (en) | 2015-07-03 | 2015-07-03 | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
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AR (1) | AR107212A1 (en) |
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CA (1) | CA2896038C (en) |
CR (1) | CR20180014A (en) |
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CN113045773B (en) * | 2021-03-16 | 2022-05-31 | 南京林业大学 | Method for in-situ inducing nano-cellulose gelatinization in streptococcus zooepidemicus fermentation process |
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US3652762A (en) | 1970-04-14 | 1972-03-28 | Ciba Geigy Corp | Pharmaceutical compositions and methods employing substituted derivatives of 2-anilinophenylacetic acids and esters |
US4517295A (en) | 1983-02-18 | 1985-05-14 | Diagnostic, Inc. | Hyaluronic acid from bacterial culture |
NO161573C (en) | 1983-11-25 | 1989-08-30 | Miles Inc | PROCEDURE FOR THE PREPARATION OF HYALURONIC ACID. |
JPS60251898A (en) * | 1984-05-25 | 1985-12-12 | Shiseido Co Ltd | Preparation of hyaluronic acid by fermentation method |
US4780414A (en) | 1985-01-18 | 1988-10-25 | Bio-Technology General Corp. | Method of producing high molecular weight sodium hyallronate by fermentation of streptococcus |
US4784990A (en) * | 1985-01-18 | 1988-11-15 | Bio-Technology General Corporation | High molecular weight sodium hyaluronate |
US5023175A (en) * | 1986-05-01 | 1991-06-11 | Kabushiki Kaisha Yakult Honsha | Novel production process of hyaluronic acid and bacterium strain therefor |
GB9024223D0 (en) * | 1990-11-07 | 1990-12-19 | Fermentech Ltd | Production of hyaluronic acid |
US5897880A (en) | 1995-09-29 | 1999-04-27 | Lam Pharmaceuticals, Llc. | Topical drug preparations |
US5952006A (en) * | 1995-09-29 | 1999-09-14 | L.A.M. Pharmaceuticals, Llc | Drug preparations for treating impotency |
US6251436B1 (en) * | 1995-09-29 | 2001-06-26 | L.A.M. Pharmaceutical Corporation | Drug preparations for treating sexual dysfunction |
US6063405A (en) | 1995-09-29 | 2000-05-16 | L.A.M. Pharmaceuticals, Llc | Sustained release delivery system |
US6387407B1 (en) | 1995-09-29 | 2002-05-14 | L.A.M. Pharmaceutical Corporation | Topical drug preparations |
AU2002366711C1 (en) * | 2001-12-21 | 2009-01-22 | Novozymes A/S | Methods for producing hyaluronan in a recombinant host cell |
KR100927579B1 (en) * | 2006-12-13 | 2009-11-23 | 주식회사 엘지생명과학 | Composition Comprising Hyalruronic Acid and/or their Salt for Treatment of Atopic Dermatitis |
WO2008094910A2 (en) * | 2007-01-30 | 2008-08-07 | Cypress Pharmaceutical, Inc. | Hyaluronate compositions |
CA2731769C (en) * | 2008-07-21 | 2013-09-10 | Otonomy, Inc. | Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders |
CN103126974B (en) * | 2011-11-30 | 2018-04-10 | 王冕 | A kind of gel |
CN103254118A (en) | 2012-02-17 | 2013-08-21 | 温州大学 | Preparation method of Hg<2+> probe |
JP6178412B2 (en) * | 2012-06-05 | 2017-08-09 | オラテック セラピューティクス リミティド ライアビリティ カンパニー | Pharmaceutical composition for treating inflammation and pain |
CA2912438A1 (en) * | 2013-04-10 | 2014-10-16 | Glycobiosciences, Inc. | Topical nutraceutical composition |
CN103254448B (en) * | 2013-05-17 | 2015-06-24 | 成都金凯生物技术有限公司 | Medical sodium hyaluronate gel and preparation method thereof |
CN103405470B (en) * | 2013-08-22 | 2016-08-10 | 北京泰克美高新技术有限公司 | Hyaluronic acid and hyaluronate are being used for treating and alleviating the application of the compositions of xerostomia |
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2015
- 2015-07-03 CA CA2896038A patent/CA2896038C/en active Active
- 2015-07-23 EP EP15178106.9A patent/EP3111925A1/en active Pending
- 2015-08-05 US US14/818,810 patent/US9821005B2/en active Active
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2016
- 2016-01-07 CN CN202210680603.5A patent/CN115025114A/en active Pending
- 2016-01-07 CN CN201610010139.3A patent/CN106309473A/en active Pending
- 2016-06-27 MX MX2016008559A patent/MX360365B/en active IP Right Grant
- 2016-06-30 WO PCT/CA2016/050774 patent/WO2017004706A1/en active Application Filing
- 2016-06-30 KR KR1020237011305A patent/KR20230050475A/en not_active Application Discontinuation
- 2016-06-30 KR KR1020187002995A patent/KR20180059748A/en not_active Application Discontinuation
- 2016-06-30 AU AU2016289095A patent/AU2016289095B2/en active Active
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- 2016-06-30 KR KR1020217004367A patent/KR20210020171A/en active Application Filing
- 2016-07-01 AR ARP160102016A patent/AR107212A1/en unknown
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2017
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- 2017-12-07 EC ECIEPI201781071A patent/ECSP17081071A/en unknown
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MX360365B (en) | 2018-10-30 |
CA2896038A1 (en) | 2016-05-03 |
AU2016289095B2 (en) | 2017-12-14 |
KR20210020171A (en) | 2021-02-23 |
CN106309473A (en) | 2017-01-11 |
KR20230050475A (en) | 2023-04-14 |
AU2016289095A1 (en) | 2017-12-07 |
CR20180014A (en) | 2018-05-29 |
US20180042957A1 (en) | 2018-02-15 |
US10322142B2 (en) | 2019-06-18 |
ECSP17081071A (en) | 2018-04-30 |
US20170020912A1 (en) | 2017-01-26 |
CN115025114A (en) | 2022-09-09 |
AR107212A1 (en) | 2018-04-11 |
MX2016008559A (en) | 2017-04-25 |
US9821005B2 (en) | 2017-11-21 |
EP3111925A1 (en) | 2017-01-04 |
WO2017004706A1 (en) | 2017-01-12 |
KR20180059748A (en) | 2018-06-05 |
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